The expository first chapters of the book are described entirely from the Soviet point of view, and a large part of the book passes before Bond himself appears onstage. SMERSH, the Soviet counterintelligence agency, plans to commit a grand act of terrorism in the intelligence field. For this, it targets British secret service agent James Bond. Due in part to his role in the defeat of Le Chiffre, Mr. Big and Hugo Drax, Bond has been listed as an enemy of the Soviet state and a "death warrant" has been issued for him. His death is planned to precipitate a major sex scandal, which will run through the world press for months and leave his and his service's reputation in tatters. Bond's killer is to be SMERSH executioner Red Grant, a psychopath whose homicidal urges coincide with the full moon. Kronsteen, SMERSH's chess-playing master planner, and Colonel Rosa Klebb, head of Operations and Executions, devise the operation. They persuade an attractive young cipher clerk, Corporal Tatiana Romanova, to falsely defect from her post in Istanbul, claiming to have fallen in love with Bond after seeing his file photograph. As an added incentive, Tatiana will provide the British with a Spektor, a Russian decoding device much coveted by MI6. She is not told the details of the plan.
An offer of the Spektor is subsequently received by MI6 in London, ostensibly from Romanova, and contains the condition that Bond collects her and the machine in Istanbul. MI6 is unsure of Romanova's story, but the prize of the Spektor is too tempting to ignore and Bond's superior, M, orders him to go to Turkey and meet her. Bond meets and quickly forms a comradeship with Darko Kerim, head of the British service's station in Turkey. Kerim takes Bond to a meal with some Gypsies, in which Bond witnesses a brutal catfight, interrupted by an attack by Soviet agents. In retaliation, Bond helps Kerim assassinate a top Bulgarian agent.
Bond duly encounters Romanova and the two plan their route out of Turkey with the Spektor. He and Kerim believe her story and in due course she, Bond and Kerim board the Orient Express with the Spektor. Bond and Kerim quickly discover three MGB agents on board travelling incognito. Kerim uses bribes and trickery to have the two taken off the train, but he is later found dead in his compartment with the body of the third agent, both having been killed by Grant. At Trieste a fellow MI6 agent, "Captain Nash", arrives on the train and Bond presumes he has been sent by M as added protection for the rest of the trip. Tatiana is suspicious of Nash, but Bond reassures her that Nash is from his own service. After dinner, at which Nash has drugged Romanova, Bond wakes up to find a gun pointing at him and Nash reveals himself to be the killer, Grant. Instead of killing Bond immediately, Grant reveals SMERSH's plan, including the detail that he is to shoot Bond through the heart and that the Spektor is booby-trapped to explode when examined. As Grant talks, Bond slips his metal cigarette case between the pages of a magazine he is holding in front of him and positions it in front of his heart to stop the bullet. After Grant fires, Bond pretends to be mortally wounded and when Grant steps over him, Bond attacks him: Grant is killed, whilst Bond and Romanova subsequently escape.
Later, in Paris, after successfully delivering Tatiana and the Spektor to his superiors, Bond encounters Rosa Klebb. She is captured but manages to kick Bond with a poisoned blade concealed in her shoe; the story ends with Bond fighting for breath and falling to the floor.