Love in the Time of Cholera opens on the day of Dr. Juvenal Urbino's death. He is a highly successful doctor who has done much for the Caribbean city in which he lives, so his death has a great effect on the city. The two who are most affected are Fermina Daza, his widow, and Florentino Ariza, the man who has been waiting for him to die for fifty-one years. Florentino was Fermina's first love; as teenagers, over a period of four years, they corresponded almost daily by mail, and they were engaged for most of that time. But after returning from a trip that her father made her take in order to forget Florentino, Fermina found that she had no feelings for him, and her love for him was just an illusion. Florentino became desperate, and when he found out that Fermina was going to marry Dr. Juvenal Urbino, he vowed to become as successful as he could while waiting for Dr. Urbino to die, so that he could win back Fermina when the time came.
Following his plan, Florentino gets a job in his dead father's riverboat company. Thanks to his undying dedication to Fermina and the help of his friend Leona, he is able to rise to the top. He uses sexual love to soften his pain over Fermina, and over his lifetime he has 622 long-term love affairs. But through all of this he never forgets Fermina, becoming more and more disturbed as he sees himself and Fermina aging, afraid that he will run out of time.
Meanwhile, Dr. Urbino and Fermina build a comfortable marriage. They understand each other perfectly and depend on each other totally, but their love is not perfect. Fermina does not like the perfection necessary in the housekeeping and is too proud ever to admit culpability. In addition, Dr. Urbino falls in love with a patient for a dizzy four months, and he cannot live with his guilt. They are happy for the most part--and certainly look happy to the public. Fermina thus is very distraught when he dies. When Florentino approaches her at the vigil for Dr. Urbino and declares his undying love, she is disgusted and throws him out.
Florentino, however, has waited too long to give up that easily. He despairs for weeks until he receives a letter from Fermina filled with hate and anger. He takes this as an opportunity to write back to her, so he begins to write letters which are impersonal musings on life, love, aging, and death, unlike anything he has written before. Fermina is moved by them, so she does not send them back. When she sees him at the memorial Mass on the anniversary of her husband's death, she thanks him for being there.
Over the next year, Florentino and Fermina slowly build a friendship via weekly visits and frequent letters. After a few personal disasters leave Fermina desperate for escape, Florentino proposes that they go on a riverboat trip. She agrees, and they embark on the trip together. While on the boat, their relationship builds slowly, but during a week when the boat has run out of fuel and is stuck unmoving in the extreme heat, they find love.
When the boat reaches its last stop, Fermina is dismayed to recognize old friends boarding the boat. She is desperate not to be seen, so Florentino speaks to the captain, and they decide to fly a yellow flag that warns of cholera on board--this will make them free to travel home in peace. The trip back is wonderful, but they both dread arrival as if it is a kind of death. They talk to the captain again, and together they decide that they will never return--they will continue sailing on their riverboat with their yellow flag waving forever.