In late 19th-century (1879) Cartagena, a river port in Colombia, Florentino Ariza (Javier Bardem) works for Lotario Thurgot (Liev Schreiber), the town's post-master. Florentino is asked to make letter deliveries to the Daza house & falls in love at first sight with Fermina Daza (Giovanna Mezzogiorno). They secretly correspond (Florentino's mother is also a romantic and supports and guides him through the tribulations of young love), and she (Guided by her aunt Escolastica (Alicia Borrachero)) eventually agrees to marry him.Feremina's father Lorenzo Daza (John Leguizamo) discovers their relationship (he objects that Fermina is too good to marry a telegraph operator and has bigger things to do in life) and sends her to stay with distant relatives (mainly her grandmother and niece) who live far away, up in the mountains, at least a few weeks away on foot. Hildebranda Sánchez (Catalina Sandino Moreno) is Fermina's cousin and her confidant. Columbia goes through Civil war and cholera, but Florentino continues to be in touch with Fermina via letters and telegrams.When she returns some years later, Fermina tells Florentino that she has realized that what is between them is just an illusion and nothing more. Florentino is heartbroken but has no bad feelings towards Fermina. Fermina agrees to marry Dr. Juvenal Urbino (Benjamin Bratt), her father's choice (Urbino had come to treat Fermina when she falls sick and determines that she is suffering from an intestinal infection and not cholera). Her father had seen Ubrino pursuing Fermina and approved of the match, so he forces Fermina to reciprocate his feelings. Fermina resists, but eventually gives in. They honeymoon in Paris.Fermina's marriage devastates Florentino, who vows to remain a virgin. His mother begs his uncle to get him a job far away where there are no letters or telegraphs. His uncle transfers him to a town which is at least 3 weeks of travel and in the middle of the Columbian jungle. On the ferry, Florentino is pulled into a cabin by a mysterious woman who has sex with him. Florentino likes the experience and returns back home to his mother.To help Florentino get over Fermina, his mother Transito Ariza (Fernanda Montenegro) throws a willing widow Nazaret (Angie Cepeda) into his bed (Nazaret's house was destroyed in the civil war and she was desperate for any kind of shelter), and Florentino discovers that sex is a very good pain reliever, one he uses to replace the opium that he had habitually smoked. Florentino begins to record and describe each of his sexual encounters, beginning with the widow, and eventually compiles over 600 entries.Urbino & Fermina, return after their 2 yr honeymoon, with Fermina pregnant. Their 50-year marriage is outwardly loving but inwardly marred by darker emotions. Fermina's mother-in-law is snobbish and hates her ordinary roots. Urbino doesn't have the courage to move out of her house and get his own place.Now a lowly clerk (He begs his uncle Don Leo (Hector Elizondo) to get him a job again & he is appointed to the board of directors in the River company of the Caribbean) (Florentino is besotted with love, and helps write poetic love letters for other lovers who can't read or write and writes business letters in rhyme), Florentino plods resolutely over many years to approach the wealth and social standing of Dr. Urbino. eventually when Uncle Don Leo dies, he appoints Florentino, his illegitimate nephew as his successor.Florentino continues to charm many girls over the years, but they are nothing more than a one-night stand for him (and neither do they expect anything more from him). Florentino still encounters Fermina at public events and Fermina wonders if she would have been happier with Florentino. One day Florentino meets Olimpia Zuleta (Ana Claudia Talancon) and ends up falling for her. But Olimpia's jealous husband finds out about her affair and kills her brutally. Florentino is devastated and loses his mother as well shortly thereafter. When Don Leo retires, he officially appoints Florentino as the President of the company.Fermina suspects that Urbino is having an affair. Urbino admits his adultery and breaks up with his mistress. Fermina leaves the house to go with live Hildebranda in the country. Urbino pursues her and brings her back to their house. Florentino is up to 622 entries in his diary.When the now-elderly doctor dies suddenly (51 years 9 months and 4 days), Florentino immediately and impertinently resumes courting Fermina. Fermina rejects Florentino to begin with. She has a full-grown daughter Ofelia and the society to contend with. Fermina meets Florentino and says she is 72 now. But Florentino convinces her that he still sees her as a 22 yr old. Ofelia objects to the budding love between Fermina and Florentino. Fermina throws Ofelia out of her house. Fermina goes on a river cruise with Florentino and admits that while Urbino was a good husband, there were more difficulties than pleasure.They kiss on the decks of the cruise boat. They end up having sex in Fermina's suite. For the return trip, Florentino gets the captain to hoist the cholera flag on the ship and this way they don't have to take on any passengers or cargo. They end up spending time together on the boat and Florentino's dream comes true after 53 years of waiting.