At the beginning of the story, Lestat grows depressed and becomes remorseful because of his vampiric nature. Although he tries to limit his victims to murderers, serial killers and other criminals, he nonetheless caves into temptation once in a while and kills an "innocent" or someone who he feels does not necessarily deserve to die. Lestat also suffers from constant nightmares concerning his late "daughter," Claudia, for whose death he blames himself.

The "coven" of vampires formed at the end of The Queen of the Damned has long since broken up, and Lestat has become extremely lonely. Among his only remaining friends is the mortal head of the Talamasca, David Talbot, who is seventy-four years old. Although Lestat has repeatedly offered David the Dark Gift, David has always refused to become a vampire and keep Lestat company through eternity. Lonely and depressed, Lestat goes to the Gobi desert at dawn in a half-hearted suicide attempt. When he does not die, he goes to David's home in England to heal.

A mysterious figure, Raglan James - the epitimous "Body Thief" of the story - approaches Lestat with what seems to be a cure for his ennui and depression. James sends Lestat several messages hinting that he has the ability to switch bodies. Eventually, he proposes to Lestat that the two of them trade bodies for a day. Against the advice of other vampires and David Talbot, Lestat jumps at the opportunity. Unfortunately, James has no intention of ever switching back, and Lestat is forced to scheme to regain his body.

Lestat nearly dies after becoming human again - his new body is wracked by pneumonia, which he ignores during a tour of Washington D.C. in the middle of winter. He is saved by the care of a nun named Gretchen. He enjoys a short love affair with Gretchen before she returns to South America, where she works in a convent, and Lestat sets out in search of his body.
Lestat seeks help from other vampires but is completely ostracized by them. Marius is extremely angry at him for leaving such a powerful body to a thief and refuses to help him. Likewise, his lover Louis turns him away when he asks Louis to make his new body into a vampire, arguing that Lestat ought to be happy to be human again. Lestat's only ally is David Talbot.

Drawing from the Talamasca's resources on the supernatural, Talbot reveals that James was a gifted psychic who once joined the order, but was kicked out for constant theft. He is a kleptomaniac who enjoys stealing for the thrill of it — it is revealed that every single thing he owns, from his house to his body, was stolen or schemed for. However, he also has major psychological problems, and his life is a series of cycles — he gets rich by theft, then often ends up in prison. Dying of cancer several years before, James tricked the inmate of a mental institution into switching bodies with him, allowing him a type of immortality.
It is James' lack of imagination and petty thievery that allow Talbot and Lestat to track him down. Despite his newfound wealth and powerful new body, James continues to steal jewelry from people. He also makes a conspicuous show of his wealth, boarding the RMS Queen Elizabeth 2, and draining victims of their blood along the ship's path. The pattern allows his pursuers to easily find him.
On the cruise ship, Lestat manages to regain his body with David's help, but the sun is rising as he performs the switch and he must immediately flee to a safe place in which to spend the day. When he awakes in the evening he finds that both James and Talbot have disappeared. He finds David in Florida and is surprised to find that his friend, despite his earlier protestations, now wants to become a vampire. However, while taking his blood, Lestat discovers a final trick — when forced out of Lestat's body, James took over Talbot's body instead of returning to his own. Lestat angrily attacks James, crushing his skull. The blow proves fatal, but only to the body.

David, meanwhile, has begun to enjoy life in his new, young body. Lestat, feeling that he has regained his "evil" nature, decides to make Talbot into a vampire against his wishes, and despite the role Talbot played in saving his life when everyone else abandoned him. After having immortality forced upon him, David again disappears. Lestat looks for him for a while, but upon having no luck he gives up and returns to New Orleans — where to his surprise he finds that David has already contacted Louis when he is confronted by the two angry vampires. But they can't stay angry for long. The book ends with the start of a new coven and plans for a trip to Rio.