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.She then appeared in The American President (1995), playing the assistant to the President of the United States.

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She appeared in an off-Broadway production of the play, Love, Loss, and What I Wore, at New York City's Westside Theatre in October 2011.

Mathis was the last girlfriend of actor River Phoenix and was with Phoenix the night he died as a result of a drug overdose while attending The Viper Room in Los Angeles, California.

Following a performance by budding musician Phoenix and Red Hot Chili Peppers guitarist John Frusciante — a performance undone by the pair’s excesses — Forrest recalls a gathering in an office of the Viper Room. River was obviously wasted and was as unsteady as a boxer who had taken one too many head shots during a 15-round bout,” Forrest recalls in the book.

“His complete lack of motor skills made me think he was drunk.

She costarred 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.

It was great fun until I felt a hand tap my shoulder and turned to see River. “Bob, I don’t feel so good,” Forrest recalls Phoenix telling him. “I still have guilt that I dismissed his worries so casually.” Shortly thereafter, a commotion erupted in the club, and Forrest rushed to the door to find Phoenix’s girlfriend, “American Psycho” actress Samantha Mathis, screaming as her boyfriend convulsed on the sidewalk.

“I think I’m OD’ing.” Also read: Mike Starr, ‘Celebrity Rehab’ Alum and Alice in Chains Bassist, Dies at 44 Forrest was doubtful that Phoenix was overdosing — “Usually you just OD and that’s it,” Forrest observes in the book — but offered to get Phoenix home. Also read: Tom Sizemore Was Once So High, He Didn’t Know There Were Cameras on ‘Celebrity Rehab’ “He was alive, because his arms and legs shook like he was having an epileptic fit,” Forrest recalls in the book.

In the autopsy report the Los Angeles Police detailed that Mathis refused several times to give more details surrounding the death of Phoenix and had told deputies at the time of Phoenix's death that she had no knowledge of his drug use.