Black Jack accepts a three million dollar fee from the young and beautiful Sayuri Crossword to treat Manabis Crossword (the Chairman of the Carosan Corporation and Sayuri's husband) on isolated windswept Raoski Island. Black Jack arrives to find a frail old man, wracked with painful spasms as all the water drains from his body leaving him weak from dehydration. Eighty doctors could find no cause, but Jack discovers that he has Kimaira, a disease endemic to the island and supposedly dormant for 150 years. However it actually surfaced 60 years earlier, infecting the Crossword family who were all killed by the villagers except the young Manabis. Manabis asks Black Jack to operate on him during a spasm to find the cause of the disease. Black Jack agrees and discovers that the Kimaira virus just as Manabis dies enabling a cure to be developed.

Six months ago while in S-city, Black Jack saves Rei Fujinami, one of four girls who is injured while ice skating. Now, during a stop-over in S-city, he encounters the same girl who asks him to treat Yumiko Inoue (Rei's friend) who is in a coma after an 80m fall. Of her other friends, Yuki was killed by a speeding car and Kaori committed suicide 10 days later. Jack examines Yumiko in the wealthy private hospital inherited by Tokio Umetani, although Umetani is more interested in car racing. Jack operates on Yumiko to remove the hematoma on her brain, assisted by the hospital surgical team. Jack discovers that the girls became addicted to mescaline from a small, spiny cactus after finding them growing on Mt. Senin and informs his friend, Police Lt. Takasugi. He accuses Umetani of cultivating the plants and attempting to kill the girls to hide his secret, however they are suddenly interrupted by syndicate operatives who abduct them. They are left on Mt. Senin with the plants ablaze and a ticking time bomb, however Jack just manages to drag himself and Umetani free before the explosion. Later, he bids a fond farewell to Rei and Takasugi.

The Federal Unites Air Force attacks the Ortega republic accusing its leader General Cruz of international criminal activities. Meanwhile, Black Jack is asked by a woman called Maria to operate on an unknown person. During transit, Ortega forces free Cruz, and Captain Maria Carnella is shot in the eye. She contacts Jack who says the patient is Cruz who is dying from cancer. On the perilous journey back to Ortega, Black Jack operates under moonlight to remove a cancerous lesion on Cruz's thyroid gland to prolong his life. Meanwhile, Federal Unites elite forces attack and the Ortega forces create a diversion, however they are defeated and Maria gives her life to save her father, General Cruz. Jack carries Cruz to the border, but he is killed under orders of Federal Unites President Kelly. Later, back home, Pinoko finds Maria Carnella's dog tags in a drawer.

Dr. Kiriko is shown to be a doctor who assists his clients to die. Black Jack is called in to help Michelle Rochasse, a movie actress who is visibly undernourished and weak, and unable to eat. After an exhaustive battery of tests Jack cannot identify the cause. Red blotches begin appearing on her skin, and she crashes her car, but she is saved by Dr. Kiriko. Jack examines Michelle and he is told by the film's director that Michelle's childhood friend, his sister Catina, developed similar symptoms before her death. The only common denominator is their childhood village of Anjou. On his way to Anjou Jack encounters the toxicologist, Dr. Kiriko who gives him information about chemical weapons from World War I stored near the village. Jack manages to isolate the parasite responsible and operates to remove it from Michelle’s brain, saving her life and enabling her to complete the movie

While on vacation, Black Jack comes across a young man called Leslie Harris on a train. Bullet wounds mysteriously appear on his body, bleed, but then disappear. Leslie has recurring dreams of seeing a woman with a child singing about the Owl of San Merida where he finds himself in a battle zone being shot. Black Jack examines him and finds barely visible signs of many earlier operations. They travel to the Republic of El Garnia, a country with over 25 years of civil war which ended 4 years earlier, and visit the village of San Merida. Leslie finds it familiar, and they meet Ernesto, the only survivor who tells the story of how he, an uncertified doctor, saved a baby by using the blood and body components of the dead woman Sanda, including her bullet-riddled skin. Suddenly the government troops arrive and arrest, then summarily shoot Ernesto for his part in the resistance. Jack is unable to save his life, leaving Leslie the only living survivor of San Merida.

Black Jack receives a large box of old Japanese currency from Saburo Taneda with an urgent request to treat his dying wife, however it was sent two years ago. Jack and Pinoko travel to Yashaga Mountain, through a snow storm, but become bogged and fall asleep. Jack awakes and sees a temple so he leaves Pinoko with a monk, Lady Kaoru, and continues by foot. He is caught in an ancient battle between the samurai Saburo Taneda and his enemies. Jack meets Princess Ikehata who ate the poisonous gamakazura fruit four years earlier rather than marry Lord Rokuyoji against her will and since then she has suffered seizures and violent fits. Abumaru, a messenger from Lady Kaoru the spurned wife of Lord Rokuyoji, visits Saburo and demands that he surrender Ikehata. Jack operates on the princes to repair an irregular heartbeat, which releases a giant snake. Saburo kills the snake which also causes the death of Lady Kaoru. Following the operation Saburo and Ikehata flee together, but are killed by Rokuyoji's troops. Meanwhile, Abumaru kills Rokuyoji in revenge for his poor treatment of Kaoru. The storm clears and Jack awakes, realizing that he has had a dream, and he is taken by Saburo to see his sick wife. Jack diagnoses that she has mesothelioma and prepares to take her to the hospital, but surprisingly finds that Saburo died two years earlier, and his wife was cared for by neighbors who resemble Kaoru and Abumaru.

Yasuhiko Shirabyoshi, the wealthy chief of surgery at the Tozai University is shocked when his fiancée, Catherine, asks for a six month postponement of their wedding, because she has volunteered to provide medical assistance for people affected by the civil war in Adentarl. Catherine encounters Jack on her way to a refugee camp, where he searches for a girl called Karen Aramis on behalf of her mother, Saranda and crime boss grandfather Patterson, because she has the hereditary heart ailment, Tetralogy of Fallot. Jack operates on her in a field hospital assisted by Catherine who travels back to New York by helicopter while Jack stays to treat the refugees. He refuses to work in the camp for free and demands one dollar per patient. Meanwhile, the immanent Dr. Stanfield calls together a panel of the International Medical Association (IMA). He proposes that Jack be granted an international medical licence, because he believes that medical ability is not a case of black or white, however Shirabyoshi objects. Jack arrives in New York, and while at a karaoke bar, Patterson is shot and rushed to hospital. Shirabyoshi refuses to allow Jack to operate without a licence and commences surgery to remove the bullets himself. However, Shirabyoshi lacks the practical experience, and he allows Jack to finish the surgery. A month later the IMA unanimously vote to grant jack a medical licence, but he is not present. Back at home, Jack receives a large package from Adentarl containing many IOUs for one dollar.

Near the remote village of San Ferna in the Andes, an ancient beech tree is about to be cut down to make way for a highway, but old man Armando protests that it protects the village. Jack receives a telephone request from Andrew, a boy whose brother Lawrence has plants beginning to sprout from his body. Jack and Pinoko travel to the outskirts of London where he examines Lawrence, but finds no clinical explanation for the plant. That night Lawrence disappears and while Jack and Andrew search for him, he appears at Jack's hotel and takes Pinoko with him to the airport from where they fly to San Ferna. Jack and Andrew follow them and reach the boys' parents' house but Lawrence has not arrived. Meanwhile, Armando is camped near the ancient tree and he hears it tell him to find the children. Jack finally finds them, and after a thorough examination he finds that a seed from a beech tree, Fagus Sieboldii, has taken root within his body and is beginning to take control. Jack operates to remove the parasitic plant, and Lawrence begins to recover. On the day the ancient tree is to be felled, Lawrence arrives and sings to it. It flowers, then disperses its seeds before it withers and dies.

A street urchin attacks and damages luxury cars, and the case is handed to Takasugi in the Juvenile Division. Investigators find a match between the youth's fingerprints and a woman known as the Love Hotel Killer who has been killing her clients. Meanwhile, Jack is called to examine Koichiro Tsuzuki, the young head of the Tsuzuki corporation who has developed a large carbuncle-like tumor on his abdomen which resembles a human face. Some nights he mysteriously disappears for hours. Meanwhile, a beautiful woman calling herself Ryuko, seduces and kills men who cheat on their wives. Later, Jack encounters Mariko, a homeless teenager, who asks him to help her wounded friend Ryuko, whom he discovers has a carbuncle similar to that of Koichiro. When Jack returns to the Tsuzuki residence he finds Ryuko there and the carbuncle then changes her back into Koichiro. Jack determines that Koichiro suffers from a dissociative identity disorder and operates to remove the tumor, but during the operation, the personality of Jun, a street urchin surfaces and he escapes. Suddenly, the police arrive to arrest Koichiro Tsuzuki who has the same fingerprints as the urchin and serial killer on suspicion of the recent murders. Jun attacks the police and is shot, transforming back into Koichiro before dies.

The D.L. Chemical company is found guilty of poisoning people who ate fish caught in the bay which were affected by the toxic waste that flowed into Mikazuki Bay. It is ordered to pay damages for many people who have died and hundreds who have suffered various symptoms as a result of heavy metal toxemia. Representatives from D.L. Chemical ask Jack to assist in helping 300 patients urgently needing surgery. Jack and Pinoko stop at a Shinto shrine, which locals call the Mermaid Shrine. It based on the story of Jiro, a fisherman fell in love with Nagi, a mermaid. Nagi prayed the Lord of the Dragon Palace to change her tail into legs so she could be with Jiro, however when she dived back into the water to find a blue pearl demonstrate her love for Jiro, she drowned. Jack and Pinoko stay a Inn and hot springs where they meet Tsukiko, a young woman crippled by the Mikazuki syndrome who sells fish for a living even though the buyers don’t eat them. Jack visits Dr. Fox at the hospital to discuss to project, but rumors circulate of an unlicensed doctor on the team, and Jack declines to work on the project. Returning home, Jack sees Tsukiko who is no longer able to walk and he performs knee replacement surgery. However, Tsukiko misses the sea, and one night she returns to the bay and drowns. When carrying out the autopsy, blue pearls are found in her duodenum which Jack keeps as a possible key to curing the Mikazuki syndrome.

Pinoko suddenly collapses and at the same time, Lady Yurie, head of the highly regarded Saionji family also collapses while rehearsing a traditional dance. Black Jack can find no cause for Pinoko's ailment, but is intrigued when called on to treat Lady Yurie from whom Jack removed a Teratoid Cystoma years ago. It is gradually revealed that the cyst was actually Lady Yurie's twin sister, growing within her body. Jack removed the small body parts which he later surgically reassembled to create Pinoko. Jack examines Lady Yurie and finds that she has had recurring malignant tumors, and her body is beginning to fail her. However, she insists on maintaining the family tradition of the head of the Saionji family performing the "Ascent of the White Heron" at the White Heron Temple every ten years. The temple's story tells of a heavenly maiden who took the form of a heron and descended to the land.

A woman collapses on Black Jack's flight to Tokyo and requires immediate emergency treatment. The airplane is redirected to South Korea, but it is a trick, and Jack is abducted and taken to the neighboring country of Anryon. Jack is pressured into treating their leader, General Che Hyoku, who is suffering from a glioma, however he is allergic to common anestheitics. Jack is also caught in the midst of a violent political struggle for power between the general’s militant son Tebyon and a revolutionary group led by his other son Jongi.