The novel focuses on the lives of four friends: Jude St. Francis, a disabled genius with a mysterious past; Willem Ragnarsson, a kind, handsome man who aspires to be an actor; Malcolm Irvine, an architect working at a prestigious firm; and Jean-Baptiste "JB" Marion, a quick-witted painter who wants to make a name in the art world. The book follows their relationships changing under the influence of success, wealth, addiction, and pride.
The novel's main focus is the enigmatic lawyer, Jude. He suffers from a damaged spine which leaves him with a limp and excruciating pain in his legs that comes and goes. Unbeknownst to his friends, he also frequently self-harms; one such bout of cutting led Willem to take him to Andy Contractor, Jude's doctor and trusted friend. It is clear that he suffers from debilitating mental trauma from his childhood.
Despite this apparent closeness with his friends, Jude finds himself unable to divulge either detail of his past or current state of mind to his roommate. Nonetheless, he thrives in his law practice, and develops a close parent-child relationship with his former professor, Harold, and his wife Julia, which results in the pair adopting him when Jude turns 30. While thankful, the time before the adoption is filled with further bouts of self-harm, as Jude believes he is inherently unworthy of affection. Meanwhile, the rest of the group finds success in their respective fields, with Willem becoming a star of theater and then film. JB finds success as an artist but also becomes addicted to crystal meth. The group stages an intervention, where JB mocks Jude by doing a crude imitation of his limp. In spite of successful treatment, and a great deal of apologizing, Jude finds it impossible to forgive JB. Willem refuses to forgive him too, causing the group to fragment, with only Malcolm remaining friends with all three of them.
It becomes clear that Jude was sexually traumatized at a very young age, making it difficult for him to engage in romantic relationships. His friends and loved ones begin questioning this isolation as he enters his forties, with Willem especially being baffled with regard to Jude's sexuality. As his loneliness grows more intense, he enters an abusive relationship with fashion executive Caleb, who is disgusted by Jude's limp and his increasing use of a wheelchair. Jude finally breaks off the relationship after Caleb rapes him, and they meet a final time when Caleb follows him to dinner with Harold, humiliates him, and then follows Jude to his apartment, where he brutally beats and rapes him, leaving him for dead. Jude nonetheless refuses to report the incident to the police, believing he deserved it. Besides Harold, only Andy – Jude's doctor and ongoing confidante – knows the truth of the failed relationship.
Although Jude's body manages to heal, the rape causes him to flash back to his childhood, wherein he was raised in a monastery and repeatedly sexually assaulted by the brothers. He recalls a period when one of the brothers, Brother Luke, ran away with him, forcing him into years of child prostitution. After he was rescued by the police, Jude was placed in state care, where the abuse continued at the hands of the counselors there. After the break-up with Caleb brings back this childhood trauma, Jude finally decides to kill himself but survives the attempt. In the aftermath, Willem comes back home and begins to live with him. Jude continues to refuse therapy but begins to tell Willem the least traumatic stories about his childhood, which Willem finds disturbing and horrifying. The two soon begin a relationship, but Jude continues to struggle with opening up, and does not enjoy having sex with him.
In an attempt to curb his cutting, Jude decides to instead burn himself as a form of self-harm, but accidentally inflicts third-degree burns that require a skin graft. The wound is so severe that Andy tells him he has to tell Willem what happened, or else he will do it for him. Before Jude can tell Willem, Andy accidentally divulges the information. Willem is horrified but, after a difficult fight, Jude finally confesses that he does not enjoy sex, and tells Willem about the years of sexual and physical abuse he endured. Jude also reveals that he escaped state care at age 14 and hitchhiked, performing sexual acts as payment to drivers. He also explains to Willem that the damage to his legs was caused by a man called Dr. Traylor, who picked Jude up and held him captive while he cured him of venereal disease, assaulted him, and eventually ran him over with his car.
The relationship continues, with Willem sleeping with women (and not with Jude) . The two settle into a comfortable life together, which is shaken when Jude's legs become worse, and he must reluctantly amputate. He manages to learn to walk again with his new prosthetics, and the pair enter a period of their life which Willem dubs "The Happy Years". However, while picking up Malcolm and his wife from the train station for a visit, Willem is involved in a car accident with a drunk driver, which kills all three occupants. With his close friend and lover dead, Jude descends once again into self-destructive habits, losing such an excessive amount of weight that his remaining loved ones stage another intervention. Though they are able to get him to gain weight and to attend therapy, years of depression and despair finally overtake Jude, and he takes his own life.
