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Samantha Mathis was born in 1970 in New York, to Donald Mathis and Austrian-born Bibi Besch, an aspiring actress at the time. Her first acting job was in a commercial for baby products with her mother.Since her parents divorced when she was only three years old, Samantha was very exposed to the acting industry from a very young age, which made her almost destined to become an actress.She took a little over a year off from acting after her mother died in 1996 from breast cancer.Mathis later appeared in American Psycho (2000), a film adaptation of Bret Easton Ellis's 1991 novel of the same name.Mathis met actor River Phoenix on the set of The Thing Called Love (1993) and the two started a relationship.She was with Phoenix on October 31, 1993, the night he died at Cedars-Sinai Hospital of a drug overdose after collapsing outside West Hollywood's Viper Room.Mathis and Slater had voice roles in the animated film Fern Gully: The Last Rainforest (1992).
She starred in the TNT television miniseries The Mists of Avalon (2001).
The daughter of actress Bibi Besch, Mathis made her film debut in Pump Up the Volume (1990), and later co-starred or appeared in such films as Little Women (1994), The American President (1995), Broken Arrow (1996), American Psycho (2000), The Punisher (2004), and Atlas Shrugged: Part II (2012).
She co-starred in the television series Aaron's Way and Knightwatch from 1988 to 1989.
Her first starring role in a feature film was that of Nora in Pump Up the Volume (1990), opposite Christian Slater, whom she briefly dated at the time.
Mathis appeared in the television movies Extreme Close-up, 83 Hours 'til Dawn, and To My Daughter in 1990.She then appeared in The American President (1995), playing the assistant to the President of the United States.