Dismissed by some of the era's more conservative critics as pornographic at the time of its first publication in February 1968, the book 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. In 1974 Vidal published a sequel, Myron.
In the climactic scene of the novel (Ch.28), Myra has had Rusty come to the infirmary ("a small antiseptic white room with glass cabinets containing all sorts of drugs and wicked-looking instruments") at 10 p.m. under the pretext of having to conduct a medical examination. After tying Rusty face down to the examination table, she at first humiliates him verbally by asking him very personal questions about his sex life and commenting, in rather drastic tones, on the allegedly moderate size of his penis ("I'm afraid, Rusty, that you've been somewhat oversold on the campus. Poor Mary-Ann. That's a boy's equipment."). Finally, she blackmails the student into letting her tie him up to the examination table. She then shocks him by using a strap-on dildo to anally rape him ("Now remember the secret is to relax entirely. Otherwise you could be seriously hurt."). Afterwards, she even makes him thank her for the trouble she has taken.
Only towards the end of the novel does the reader learn about Myra's secret: Pretending that she is Myron Breckinridge's widow, she demands from her uncle, who owns the Academy, half of what he has built up, while in fact she was Myron, has had sexual reassignment surgery and only poses as his widow. However, when she has a car accident and is hospitalized, Myra is unable to acquire her necessary hormones and is forced to have her silicone breasts removed. In the end, she is transformed back into Myron, and in this state he settles into a peaceful, absurdly cheerful life with Mary-Ann.
The subplot of Myra Breckinridge revolves around the character of Letitia Van Allen (Mae West in the movie), an aging, sexually precocious talent scout 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…") have landed her in hospital, half paralyzed, at the same time as Myra.
The spirit of the times is also well reflected in another, earlier chapter (Ch.14) of Myra Breckinridge where Myra attends an orgy arranged by one of the students. She goes there, intending to be an observer only, but suffers a "rude intrusion" by a member of the band The Four Skins, from which she derives a perverse, masochistic enjoyment. At an earlier regular party, after "mixing gin and marijuana", she eventually gets "stoned out of her head" and passes out in a bathroom.