Jeff Daniels as Ed Saxon, a college professor, wakes up to find his wife has not returned to their Seattle home. He takes some mysterious pills, then calls one of his wife's friends, Susie, Molly Price — who suggests that he should be worried and to contact the hospital, but they have no record of his wife being admitted. After further conferring with Susie, he decides to call the police. When Gil Bellows as Detective Derm arrives, Derm takes pills similar to Saxon's. They search his wife’s workplace and listen to a string of messages on the answering machine. George Simian, Julian McMahon, has left a message inquiring about his wife, and Derm notes that her abandoned car was found near Simian's house. Saxon also has to deal with the college, irritated that he didn’t show up to teach his class, which leads one of his students, Sadie, Emily Bergl to also leave a message.
Saxon experiences a series of unsettling hallucinations and blackouts, with time skipping forward in startling bursts. He endures a mounting storm of calls from work, which he blows off; an abusive message from George Simian, followed by a tense confrontation; and a visit from Sadie, who is worried about his unexplained absences. Saxon refuses to tell Sadie the truth about his missing wife, insisting she’s visiting her mother, and he helps her with a change of clothes after she leaves. After Sadie departs, Derm returns, pressing to search the house for clues. Derm discovers Sadie’s bloody shirt and seems satisfied with Saxon’s explanation. Derm also finds a diary his wife kept, a detail Saxon hadn’t known about. In the diary, Saxon’s wife writes of mixed emotions toward him—pity, contempt, and fear. Despite his promise to turn the diary over, Saxon burns it.
Geoffrey Costas, Zach Grenier a psychiatrist who leads a victim support group, visits Saxon and offers comfort. Saxon initially resists, then asks for stronger medication to counter long-term insomnia. Even with powerful drugs, he does not seem to sleep and continues to suffer more blackouts and vivid hallucinations. Sadie returns to his house, worried about more missed classes, but Susie interrupts them. Saxon lashes out, telling Susie that Sadie is just a student, and when Sadie finally speaks of loneliness and admiration for Saxon’s poetry, a tentative connection begins to form, culminating in a aborted moment that leaves Sadie humiliated and confused.
Derm calls with grave news: they have found Saxon’s wife’s body. Depressed, Saxon welcomes a chance to talk to Costas again. They discuss how trauma can fuel inappropriate guilt, and Costas convinces Saxon to allow him to speak to the police on his behalf. But the police reveal that they have not found the wife’s body after all, a twist that deepens mistrust and pushes Costas and Derm to suspect Saxon more than ever. More hallucinations blur the line between reality and illusion, and Saxon becomes convinced that he might be responsible for something terrible. George Simian, who had previously assaulted Saxon, returns to the house, enraged and intent on killing him. In a burst of desperate self-preservation, Saxon kills Simian, then, overcome by guilt, swallows every pill he can find. Derm arrives at the scene and kneels in front of Saxon as the truth hangs in the air, with Saxon in denial that he killed anyone. The bathroom fills with blood as the scene crescendos: the bathtub overflows, and Saxon sees his wife playing the piano.
