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`I Me Aur Main` stars John Abraham who plays the role of Ishaan- a charismatic, good-looking music producer from Mumbai. Ishaan lives a sheltered existence, is the apple of his mother`s (Zarina Wahab) eye and his elder sister, Shivani (Mini Mathur) is very protective about him. He stays at his girlfriend Anushka`s (Chitrangda Singh`s) house. One day, Ishaan`s life falls apart, his girlfriend throws him out of her house and he gets fired at work.
He then moves into a new apartment and befriends his neighbor, Gauri, (Prachi Desai) who makes him realize the importance of relationships. Consequently, Ishaan falls in love with Gauri and has to choose between his love that transformed him or take responsibility of his past actions.