At the start of the novel, Oedipa Maas is named executrix of the estate of her ex-boyfriend Pierce Inverarity, a California real estate mogul. We learn that Oedipa leads a life surrounded by a number of strange male figures. Her husband Wendell "Mucho" Maas is an extremely sensitive ex-used car salesman who now works as a DJ. Her psychotherapist, Dr. Hilarius, wants her to take part in an experiment on the effect of hallucinogenic drugs, and the family lawyer— Roseman—wants her to run away with him.
Oedipa is confused about the whole business with the estate. Thinking back on a time she went to Mexico with Inverarity, she imagines that it was a failed escape, though she doesn't know what it was an escape from.
Oedipa drives down to San Narciso to meet the co-executor of the estate, a lawyer named Metzger. As she drives, she experiences the sense that there is a revelation just beyond her reach. Oedipa and Metzger rendezvous at a hotel called Echo Courts. They watch a movie that Metzger starred in when he was a childhood actor named Baby Igor. In a super absurd scene, Metzger seduces Oedipa by having her play a game called Strip Botticelli with him. The two of them have sex in the hotel while the hotel manager's band, the Paranoids, serenade them from out by the pool. Afterward, Metzger reveals that Inverarity predicted the two of them would sleep together and Oedipa begins to cry.
At this point, the plot quickly grows much more convoluted and ri-diculous.
First, Oedipa and Metzger go to a bar called the Scope, where they meet a strange guy named Mike Fallopian, president of the right-wing libertarian group the Peter Pinguid Society. The Society is strongly opposed to the government monopoly on mail, and so is using the inter-office delivery service of Yoyodyne, a huge aerospace company based in San Narciso, to communicate with one another. In the bathroom, Oedipa sees a symbol that she will later realize is a muted post horn as well as the acronym WASTE.
The next day, Oedipa and Metzger travel to a resort Inverarity used to own, where they meet a bizarre lawyer buddy of Metzger's named Manny Di Presso. Manny tells them about a lawsuit his client wants to bring against the Inverarity Estate, which has to do with the fact that his client dredged up the bones of American GI's in a lake in Italy and sold them to Inverarity to be used in cigarette filters. Apparently Inverarity never paid Di Presso's client.
One of the Paranoids overhears the conversation and says the whole thing sounds a lot like a Jacobian Revenge Play called The Courier's Tragedy. The next night, Oedipa makes Metzger take her to go see the play. The play's plot echoes recent events in strange ways. It revolves around a usurped duchy, whose elite military men were massacred and thrown in a lake. Their bones were later turned into ink.
But that's not the only spookily familiar plot point in the play. The betrayed Duke's son wants to get revenge, and almost does, except that he is in disguise as a Thurn and Taxis mail courier. (BTW—Thurn and Taxis was a real organization that had a monopoly on mail in Europe from 1300 to 1867.) A rival mail organization, the Trystero, takes the man's disguise at face value and brutally murders him. After the play, Oedipa tries to get some hints at its meaning from the director, Randolph Driblette, but he tells her not to read too much into it.
Oedipa goes back and rereads Inverarity's will in an attempt to make herself useful. She travels to a stockholder's meeting at Yoyodyne, and gets lost in the plant, happening on a disgruntled engineer named Stanley Koteks who is sketching the muted post horn when she approaches. Dum dum dummm. Koteks is obsessed with Yoyodyne's patent clause, which claims rights to its employee's inventions. He tells her about a modern inventor at Berkeley named John Nefastis who has built a fantastic-sounding perpetual motion machine by implementing Maxwell's Demon.
Oedipa tries to press Koteks for information about WASTE, but he clams up. Thinking of Nefastis and of the publisher that printed The Courier's Tragedy, Oedipa resolves to make a trip to Berkeley.
Oedipa's next obsession is with a historical marker she saw near Inverarity's resort, which claims that some Wells Fargo employees were massacred by a bunch of men dressed in black in 1853. She immediately thinks of the Trystero.
Stopping randomly at Vesperhaven Nursery Home, Oedipa meets an old man named Mr. Thoth whose grandfather was attacked by some men dressed in black when he was a courier for the Pony Express. Thoth's grandfather cut off one of their fingers in the fight, and on it was a ring with the symbol of the muted post horn. The coincidences continue to mount around Oedipa, but she has no idea what to make of them. (And neither do we!)
Soon after visiting Thoth, Oedipa receives a call from a stamp expert named Genghis Cohen, who is inventorying and appraising Inverarity's collection. Cohen has found some strange stamps that have been forged, some dating all the way back to the time of Thurn and Taxis, whose symbol was—surprise!—a (unmuted) post horn. Cohen and Oedipa see the possibility of an 800-year tradition of postal fraud by some group opposed to Thurn and Taxis… a group that still seems to be active in the present day.
Oedipa travels to Berkeley to track down the 1957 textbook in which The Courier's Tragedy appeared. She is shocked to find that the one line in the play that mentioned Trystero is different in the textbook, and she determines that she will go visit the English professor (back in San Narciso) who edited the textbook to determine how the word "Trystero" found its way into Jacobean Revenge Plays.
But first Oedipa goes to visit John Nefastis to see if she is a "sensitive," one of the special people who can make Nefastis's perpetual motion machine work. Nefastis explains Maxwell's Demon to her, and then she is left staring at a picture of John Clark Maxwell. It doesn't work— big surprise!—and Oedipa decides that Nefastis is a nut. When he asks her to have sex with him while watching the evening news broadcast on China, it only confirms her suspicion. She screams and runs out.
Oedipa spends the entire night wandering around San Francisco, and as the night goes on she becomes increasingly convinced that she is hallucinating. First she wanders into a gay bar called The Greek Way where she meets a man wearing the WASTE symbol. He tells her that he is part of an organization called "Inamorati Anonymous," which helps people kick the addiction to love and which used the muted post horn as its symbol. As the night continues, Oedipa sees the WASTE symbol everywhere she looks. Late in the night, a homeless sailor asks her to send something for him via WASTE, and he tells her where a mailbox is. Oedipa goes there and then follows the courier along his route. Inexplicably, he takes her all the way back to Nefastis's house, and she realizes that twenty-four hours have passed.
The next day, Oedipa goes to see Dr. Hilarius, hoping he will tell her there is no Trystero and that she is just crazy. As it turns out, Hilarius himself has gone insane. He reveals that he was a Nazi at Buchenwald who took part in experiments to induce insanity in Jews. Hilarius claims that practicing Freudian psychology was his way of doing penance. The police break in and take Hilarius.
Oedipa's husband Mucho arrives a few minutes later reporting on the event on behalf of his radio station, KCUF. When Oedipa and Mucho go out to dinner that night, Mucho reveals that Hilarious gave him LSD and that he has been taking it ever since. Oedipa realizes that Mucho has also lost his mind, and decides to head back down to San Narciso to track down the English professor by herself.
When she gets there, Professor Emory Bortz announces that Randolph Driblette, director of The Courier's Tragedy, recently committed suicide by walking into the Pacific Ocean. Bortz gives Oedipa access to all of his material having to do with the play, and she manages to piece together the story of the Tristero from their origins in the late sixteenth century to their journey to America during the Civil War. Excited, Oedipa goes to see Mike Fallopian and tell him what she has found out. But Fallopian suggests that perhaps it is all just a hoax, and that someone (perhaps Inverarity) is playing a joke on Oedipa. She becomes angry, but admits to herself that he might be right… and begins to worry that she is losing her mind.
At this point, Oedipa is simply doing her best to hold it together, and she begins to lose interest in the Tristero. Yet Genghis Cohen keeps revealing forgeries done by the Tristero, and certain details do seem to fall into place.
One day, Cohen tells Oedipa that the forgeries will be sold at an estate auction as lot 49. Moreover, he reveals that a mysterious bidder has emerged, and both Oedipa and Cohen suspect that the bidder is from Tristero. Oedipa attends the auction with Cohen and the novel ends as she settles back in her seat to await the crying of lot 49.