Matthew Hiller (Rob Morrow), an American doctor from a Detroit working-class background, and Silvia Dalessandro (Matilda May), an Italian doctor whose father presides over an industrial empire, seem to be a mismatched young couple.
It's 1982 when Matthew and Silvia meet in Paris to volunteer with Medecin Internationale, an organization headed by Francois Pelletier, which places doctors in poverty-stricken and sometimes war-torn areas of Africa.
Silvia is an only child and the apple of her father's eye. Her father disapproves of her career in medicine and wants her to come back to settle down in Italy. He has even selected a prospective husband for her, Nico, the son of an Italian magnate. Silvia's father goes so far as to offer Francois Pelletier $1 million to reject Silvia's attempt to join Medecin Internationale, but Francois rejects the bribe.
Matthew and Silvia fall in love in Paris, and their romance continues after they arrive in Gamba, a country torn by civil war. The couple decides to take a weekend break and travel on a hazardous journey to Gamba City. After a romantic interlude, they are ambushed, and Matthew is shot in the head. If he's to survive, he'll have to be airlifted to Gamba City and back to Europe for immediate treatment. Silvia's father agrees to facilitate the rescue, on the one condition that she has to marry Nico. Silvia agrees.
While Silvia married a man she didn't love in order to save Matthew's life, a shadow was cast over Matthew when he lost her. He stopped playing the piano he loved so much because the music brought back painful memories of Silvia. He consigned himself to a life of bachelorhood until Evie (Marisa Tomei), his recently divorced best friend of 20 years, becomes his lover when their paths cross in Rome. Evie and Matthew fall passionately in love, get married, and raise Evie's two kids, 10 year-old Lily and 12 year-old Rachel.
In 1998, Silvia visits Matthew in New York, where he is a doctor and medical researcher. She reveals that she is seeking treatment for a brain tumor and knows Matthew has been working in that field specifically, searching for the precise molecular match that could be used to reverse a tumor: a retrovirus.
Matthew has trouble absorbing this crushing reality. His tumor-eradicating procedure is not a sure thing, yet it represents Silvia's last chance to live. Before the operation can take place, she dies in his arms. Matthew remembers Silvia's words: "What is it that really matters in the end? Only love..."