Eun-suh is the most popular girl in class, which incites the jealousy of her rival, Choi Shin-ae (Lee Ae-jung).

Ten years later, Joon-suh (Song Seung-heon) returns to South Korea as a successful artist.

He encounters his old friend, Han Tae-seok (Won Bin), who stays at the hotel where Eun-suh (Song Hye-kyo) works as a telephone receptionist.

Tae-seok, (who doesn't know about the brother and sister mix-up) falls in love with Eun-suh and manipulates her until she is fired from her job.

One day Eun-suh sees Joon-suh and follows him to the beach where he is with his fiancée Yumi (Han Na-na) and Tae-seok.

As a fight between Joon-suh and Tae-seok erupts over their love for Eun-suh, she discovers she has leukemia (the same fatal condition that killed her biological father).

However, Joon-suh, dazed and grief-stricken by the death of his love, is struck by a truck in the same place as Eun-suh's accident during her teenage years.

The 13-track soundtrack for Autumn in My Heart includes Jung Il-young's heartfelt ballads "Reason", "Prayer" and "In My Dream" as well as the main flute theme and the guitar and piano versions of some of the songs.

A song played during emotional scenes, but excluded from the soundtrack, was "Return to Love" by Kevin Kern.