After the funeral of their friend and former lover Molly Lane, two men, Vernon Halliday, an editor and Clive Linley, a composer, make a pact that if either of them should start to deteriorate in health, the other would arrange for an assisted suicide. Amsterdam quickly becomes a morality tale, as a scandal arises involving a politician that divides the two friends. They become enemies, but neither forgets the pact. The disagreement between the two former friends is what leads to their downfall while the politician finds success.
The book begins with the funeral of artist Molly Lane. Guests at the funeral include British Foreign Secretary Julian Garmony, newspaper editor Vernon Halliday, and composer Clive Linley. The three share certain attributes: each has a very high opinion of himself, each was at some time Molly's lover, and each regards the dead woman's husband, George, with a mixture of amusement and contempt.
Clive and Vernon muse upon Molly's death. It seems she had some kind of rapid-onset brain disease (not specified) that left her helpless and mad. Neither man can understand her attraction to Julian Garmony, the right-wing Foreign Secretary who is about to challenge his party's leadership.
Clive returns home to continue work on a symphony he has been commissioned to write for the forthcoming millennium. Much of the work is complete, save the crucial signature melody. He resolves to go walking in the Lake District, as this tends to inspire him.
Vernon is the editor of a newspaper whose readership is diminishing. He is trying to change the content of the paper to be more sensationalist. George, Molly's husband, gives him a golden opportunity, but he and Clive argue furiously about the moral responsibility of the act.
In the Lake District, Clive faces a difficult moral decision himself. He chooses to walk away from a potentially dangerous situation he could have helped with, because his elusive melody, the crucial notes, have arisen and he has to get them down. Instead of helping, he crouches unseen besides a rock and writes his music.
During the course of the book Clive and Vernon become mortal enemies bent on exacting revenge. The consequences of their decisions, and a pact made between them, lead them both to Amsterdam where the novel's dénouement plays out.