D’Souza made her debut in Bollywood in 2003. Her first Hindi film was Tujhe Meri Kasam opposite Ritesh Deshmukh. She left Bollywood for a while to concentrate on South Indian films. She first hit the lime-light with a Parker Pen commercial with Amitabh Bachchan and further did a Fair and Lovely 2003 Cricket World Cup ad with Krishnamachari Srikkanth. She was also a part of Mani Ratnam’s stage show, Netru, Indru, Naalai.

The Tamil director, Shankar, was very much impressed with her performance in both the ads and cast her in a leading role in his Tamil film Boys in 2003 which was a huge success.

She made her Telugu debut with Sathyam opposite Sumanth, which went on to become a blockbuster. Subsequently, she acted in several films which raised her profile in south India. She acted in successful telugu films like Happy, and Sye. She followed it up with a pairing with actor Venkatesh in Subhash Chandra Bose which met with disappointment at the box-office.

Her second Hindi movie was Masti and was also opposite Ritesh. This film was a moderate success.She then played the role of Haasini in the Telugu film, Bommarillu, which also starred Siddharth Narayan in the lead. This movie was one of the biggest hits in her career and earned her critical acclaim and wide recognition. She won the Filmfare Award as the Best Actress for her performance, besides other awards. Her character of Haasini earned rave reviews and this made her the favourite choice for that role in the remakes of Bommarillu in other languages. It was remade in Tamil as Santhosh Subramaniam in which Genelia was cast as heroine again.
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