New York City, 1985. A gay couple's relationship is rocked by the revelation that one has AIDS; a young man named Joe Pitts is offered a job by conservative icon Roy Cohn...who also learns he has AIDS.

Louis abandons a hospitalized Prior; Joe and Roy confide in each other over drinks. Later, Prior hears voices from his hospital bed while Louis solicits sex from strangers, and Joe makes a drunken confession to his mother.

Prior returns home and is visited by a pair of spectral namesake ancestors who herald the arrival of the messenger; a tussle with Joe leaves Roy with the ghost of Ethel Rosenberg. Later, Joe and Louis hook up in Central Park while Prior meets the angelic messenger.

While Joe is being seduced by Louis, Prior is being aroused by the baffled Angel. Meanwhile, Roy's health worsens; Harper's hallucination is interrupted by reality; Prior tells Belize about his divine mission; and Hannah tries to help Harper.

Louis arranges a meeting with Prior; Joe visits Roy in the hospital and gets an unwelcome father's blessing; Prior drags Belize to the courthouse for a surprise meeting with the clerk and later strikes up a friendship with Hannah. High on morphine, Roy paints a different picture of heaven.

A fight with Joe leaves Louis badly scarred; Roy plays a final practical joke on Ethel; Prior wrestles the Angel and then addresses a review board in Heaven; Harper heads out West; Prior, outliving his diagnosis, pays a visit to his favorite angel and vows to keep living--free of secrets.