The novel centers around the three principal characters: Pete Bondurant, a former Los Angeles County sheriff's deputy who presently works for billionaire Howard Hughes and runs small-time shakedowns; Kemper Boyd, an FBI agent who covets wealth and power; and Ward Littell, another FBI agent who is Boyd's friend and former partner.

Although assigned to monitor communist activities, Littell's abiding hatred of organized crime leads him to vie for a spot on the Bureau's Top Hoodlum Squad.

The three men plot to entrap John F. Kennedy with a call girl; Boyd and Littell for J. Edgar Hoover, Bondurant for Hughes.

Bondurant and Boyd ultimately collaborate with the CIA, the mob (seeking to retake its now-nationalized casinos in Havana) and far right Cuban refugees plotting to overthrow Fidel Castro's regime.

After a sham visit, Boyd naturally encourages the president to authorize the mission, promising Kennedy that it will guarantee his re-election.

The Bay of Pigs Invasion is authorized, although Kennedy second-guesses its wisdom and refuses to provide the air support that the Cadre believes necessary.

In the wake of the Bay of Pigs fiasco, Boyd and Bondurant encourage the mob to authorize an assassination attempt on Castro.

In collusion with Littell, Bondurant begins running a wiretap hoping to catch President Kennedy having an affair with a woman they have set up.

Boyd, Bondurant and Littell plot to assassinate Kennedy during a motorcade in Miami and arrange the logistics to frame right-wing radicals.

Littell confronts Robert Kennedy with evidence of his father's collusion with the mob, with the added intent that it will serve as an after-the-fact explanation of why the president would be killed.

The book ends at 12:30 PM, as Kennedy's motorcade drives through Dealey Plaza, with Bondurant closing his eyes, awaiting the shots and screams.

He bears superficial resemblances to historical figures Fred Otash,[2] (so-called "private-eye to the stars") and Robert Maheu, (who worked for both Hughes and Jimmy Hoffa during the time frame depicted in the book).

This assignment leads to CIA contacts, as well as employment to influence the future President Kennedy to take an anti-Castro stance in his Cuban policy.

Boyd also bears a resemblance to Robert Maheu, a close friend of the Kennedy brothers and former FBI agent who admitted to involvement in a conspiracy to kill Fidel Castro and has been linked to the JFK assassination.

In 2008, Daily Variety reported that HBO, along with Tom Hanks's production company, Playtone, were developing American Tabloid and The Cold Six Thousand for either a mini-series or ongoing series.