Myra Breckinridge was dismissed by some of the era's more conservative critics as pornographic at the time of its first publication in February 1968; nevertheless, the novel immediately became a worldwide bestseller and has since come to be considered a classic in some circles. "It is tempting to argue that Vidal said more to subvert the dominant rules of sex and gender in Myra than is contained in a shelf of queer theory treatises," wrote Dennis Altman. Critic Harold Bloom cites the novel as a canonical work in his book The Western Canon. Vidal called Myra his favorite of his books, and published a sequel, Myron, in 1974.
The novel was adapted into a 1970 film of the same name, which was universally panned. Vidal disowned the film, calling it "an awful joke".
In his 1995 memoir Palimpsest, Vidal said the voice of Myra may have been inspired by the "megalomania" of Anaïs Nin's diaries.
Myra Breckinridge is an attractive young woman with a mission. She is a film buff with a special interest in the Golden Age of Hollywood—in particular the 1940s—and the writings of real-life film critic Parker Tyler. She comes to the Academy for Aspiring Young Actors and Actresses, owned by her deceased husband Myron's uncle, Buck Loner. Myra gets a job teaching, not just her regular classes (Posture and Empathy), but also, as part of the hidden curriculum, female dominance. Myra selects as her first victim one of the "studs" at the Academy, a straight young man called Rusty Godowsky, and sets out to alienate him from his beautiful girlfriend Mary-Ann Pringle. She lures Rusty to the school infirmary, where she verbally abuses him, ties him to an exam table and anally rapes him with a strap-on dildo. Later, after she is injured in a car crash, it is learned that Myra is Myron, still in the process of sexual reassignment surgery; unable to obtain hormones, Myra reverts to Myron, and, as a result of the injuries she has sustained, is forced to have her breast implants removed. Now a male eunuch, Myron decides to settle down with Mary-Ann.
The subplot of Myra Breckinridge revolves around the character of Letitia Van Allen, an aging, sexually voracious talent scout whom Myra meets and befriends at the academy, whose office boasts a four-poster bed and whose kinky sexual practices ("Those small attentions a girl like me cherishes… a lighted cigarette stubbed out on my derrière, a complete beating with his great thick heavy leather belt…") landed her in hospital, "half paralyzed", at the same time Myra finds herself there towards the end of the novel.