- Suffered a serious mental and emotional breakdown during the problem-plagued shoot of the James Cameron film The Abyss (1989).
- Replaced Robin Wright, due to pregnancy, as Maid Marion in Robin Hood: Prince of Thieves (1991) with Kevin Costner.
- Once trained for a career as an opera singer.
- Was neighbors with Alan Rickman in London in the early 90's. They worked together in January Man and Robin Hood Prince of Thieves.
- Was nominated for Broadway's 2003 Tony Award as Best Actress (Musical) for portraying the Aldonza/Dulcinea character in a revival of "Man of La Mancha."
- Sons Jack O'Connor (born 1992) and Declan O'Connor (born 1997) with Pat O'Connor.
- Listed as one of twelve "Promising New Actors of 1986" in John Willis' Screen World, Vol. 38.
- Of all the people ever to be nominated for an Academy Award for acting, Mastrantonio has the longest name.
- Graduated from Oak Park River Forest High School.
- She is a niece of the late screenwriter and actor Frank Ray Perilli, as her paternal aunt, Julia Mastrantonio was once married to him.
- Currently starring as Aldonza in the Broadway revival of "Man of LaMancha" at the Martin Beck Theatre (December 2002)
- Appearing in 'Grand Hotel' at the Donmar Warehouse in London, UK (December 2004)
- Is one of five sisters, she has four older, and one younger.
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