Her screen debut came in the 1999 film Varsity Blues, followed by the horror films House on Haunted Hill and Final Destination. Major supporting roles in the comedy Legally Blonde and the romantic comedy A Lot Like Love led her to lead roles as the titular character in the Bollywood film Marigold and in the 2009 thriller Obsessed. Larter achieved wider fame after her portrayal of video game heroine Claire Redfield in the successful films, Resident Evil: Extinction and Resident Evil: Afterlife.
Larter frequently appears in "Hot" lists compiled by Maxim, FHM and Stuff as well as People magazine's "Best Dressed List" in 2007. After a three year relationship, Larter married actor Hayes MacArthur in a small ceremony in Maine in August 2009 and is expecting her first child, due winter 2010.
Larter reprised her role as Claire Redfield in Resident Evil: Afterlife, which was filmed in 3D and directed by Paul W.S. Anderson. She attended WonderCon and Comic Con to promote the movie. In an interview with JoBlo.com, Larter talked about her role in the film: "I guess people liked me as her...I'm excited that they brought me back. I love working with Milla, and it's also very excited to have Paul back directing this. To work with the man who really created this world and this vision was what excited me about joining this next installment." The movie was not well received by critics with the Philadelphia Inquirer stating the movie "lacks the humanity - interesting characters, funny one-liners - that made its predecessors enjoyable B-movies." The movie was an international success nonetheless, earning $259 million worldwide and becoming Larter's highest grossing picture to date. As of October 17, 2010, Larter's films have grossed a total of $552 million domestically.
Larter and Jovovich (left) promoting Resident Evil: Afterlife at Comic Con 2010
She is linked to the role of Col. Virginia Lake in the big-screen adaptation of UFO which stars Joshua Jackson. She also appeared as the title character in a short film for Absolut Vodka entitled Lemon Drop.
While at WonderCon, Larter commented on Heroes' possible fifth season. "I think that we'll be back...I think that there are still stories that need to be told." NBC announced the show's cancellation on May 14, 2010