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Set in the 1920s and 1930s, the film focuses on Leonard Zelig, a nondescript man who has the ability to transform his appearance to that of the people who surround him. He is observed at a party by F. Scott Fitzgerald, who notices that while mingling with the guests, Zelig sings the praises of the affluent classes in a refined, snobbish accent, but while in the kitchen with the servants, he seethes with rage at the fat cats in a thick proletarian voice. He soon gains international fame as a "human chameleon".
Dr. Eudora Fletcher (Mia Farrow) is a psychiatrist who wants to help Zelig with this strange disorder when he is admitted to her hospital. Through the use of hypnotism, she discovers Zelig yearns for approval so strongly he physically changes to fit in with those around him. Dr. Fletcher's determination allows her to cure Zelig, but not without complications; on the road to recovery, he temporarily develops a personality which is intolerant of other people's opinions.
Dr. Fletcher realizes she is falling in love with Zelig. Due to the media coverage of the case, both patient and doctor become part of the popular culture of their time. However, fame is the main cause of their division; the same society that made Zelig a hero destroys him.
Zelig's illness returns, and he tries to fit in once more. Numerous women claim he married them, and he disappears. Dr. Fletcher finds ...