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The historical backdrop for this novel is the Second World War in Northern Africa and Italy. Hana, a young Canadian Army nurse, lives in the abandoned Villa San Girolamo in Italy, which is filled with hidden, undetonated bombs. In her care is the man nicknamed "the English patient," of whom all she knows is that he was burned beyond recognition in a plane crash before being taken to the hospital by a Bedouin tribe. He also claimed to be English. The only possession that the patient has is a copy of Herodotus' histories that survived the fire. He has annotated these histories and is constantly remembering his explorations in the desert in great detail, but cannot state his own name. The patient is, in fact, László de Almásy, a Hungarian desert explorer who was part of a British cartography group. He chose, however, to erase his identity and nationality.
Caravaggio, a Canadian who served in Britain's foreign intelligence service since the late 1930s, was a friend of Hana's father, who died in the war. Caravaggio, who entered the world of spying because of his skill as a thief, comes to the villa in search of Hana. He overheard in another hospital that she was there taking care of a burned patient. Caravaggio bears physical and psychological scars; he was deliberately left behind to spy on the German forces and was eventually caught, interrogated and tortured, his thumbs having been cut off. Seeking vengeance three years later, Caravaggio (like Almásy) is addicted to morphine, which Hana supplies.
One day, while Hana is playing the piano, two British soldiers enter the villa. One of the soldiers is Kip, an Indian Sikh who has been trained as a sapper or combat engineer, specializing in bomb and ordinance disposal. Kip explains that the Germans often booby-trapped musical instruments with bombs, and that he will stay in the villa to rid it of its dangers. Kip and the English Patient immediately become friends.
Prompted to tell his story, the Patient begins to reveal all: An English gentleman, Geoffrey Clifton and his wife, Katharine, accompanied the patient's desert exploration team. The Patient's job was to draw maps of the desert, and the Cliftons' plane made this job easier. Almásy fell in love with Katharine Clifton one night as she read from Herodotus' histories aloud around a campfire. They soon began a very intense affair, but in 1938, Katharine cut it off, claiming that Geoffrey would go mad if he discovered them.
When World War II broke out in 1939, the members of the exploration team decided to pack up base camp, and Geoffrey Clifton offered to pick up Almásy in his plane, and takes Katharine with him. However, Geoffrey turns around and crashes his plane in an effort to kill all three of them, revealing he had known about the affair. Geoffrey died immediately; Katharine survived, but was horribly injured. Almásy took her to "the cave of swimmers", a place the exploration team had previously discovered, and covered her with a parachute so he could leave to find help. After three days, he reached a town, but the British were suspicious of him because he was incoherent and had a foreign surname. They locked him up as a spy.
When Almásy finally escaped, he knew it was too late to save Katharine, so he allowed himself to be captured by the Germans, helping their spy cross the desert into Cairo. He then returns to collect Katherine's body; however while flying over the desert, the aircraft is observed by Germans and shot down into flames. Almásy parachuted down covered in flames which was where the Bedouins found him.
Caravaggio, who had had suspicions that the Patient was not English, fills in details. Geoffrey Clifton was, in fact, an English spy and had intelligence about Almásy's affair with Katharine. He also had intelligence that Almásy was already working with the Germans.
Over time while Almásy divulges the details of his past, Kip becomes close to Hana. Kip's brother had always distrusted the West, but Kip entered the British Army willingly. He was trained as a sapper by Lord Suffolk, an English gentleman, who welcomed Kip into his family. Under Lord Suffolk's training, Kip became very skilled at his job. When Lord Suffolk and his team were killed by a bomb, Kip became separated from the world and emotionally removed from everyone. He decided to leave England and began defusing bombs in Italy. Kip's best friend, a British Army sergeant, is killed in a bomb explosion.
Kip forms a romantic relationship with Hana and uses it to reconnect to humanity. He becomes a part of a community again and begins to feel comfortable as a lover. Then he hears on the wireless that the United States have dropped the atomic bomb on Japan. Kip is convinced that they would not have dropped the bomb if the nation were white. He feels betrayed by the side he was fighting for. He becomes depressed and separates himself from everyone, including Hana. He eventually leaves.