De Medeiros made her big screen debut in "Silvestre" (1980) and her French screen debut in the Chantal Akerman segment of "Paris Seen By . . . 20 Years Later" (1984). Supporting roles in other French films followed: the historical drama "Le Moine et la Sorciere" (1987), "La Lectrice" (1988) and the multi-national drama "L'Air de Rein" (1989). She approached stardom in 1990 when she was chosen over scores of other hopefuls to play Anais Nin in the erotic literary biopic "Henry & June", her first US production.
Critical reaction to "Henry & June" was mixed and box office slow, partly because the film received an 'NC-17' rating. De Medeiros opted to return to Europe for better roles, rather than take her chances in Hollywood. She had a good part in the lush historical romance "1871" (France, 1990) and two 1991 Portuguese films, the absurdist drama "The Divine Comedy", directed by Manoel de Oliveira, and "A Idade Major". She appeared in support of a major Hollywood star, Glenn Close, who played an opera diva in Istvan Szabo's "Meeting Venus" (1991).
De Medeiros' career continued apace, with roles in France (the 1992 comedy "The Man of My Life", the 1994 dramas "Des Feux Mal Eteints" and "Les Bois Transparents/The Transparent Woods") and Spain (the 1993 comedy "Golden Balls" and the 1994 noir thriller "The Detective and Death"). She won a Venice Film Festival Award for her role as a girl suffering through familial disaster in "Two Brothers, My Sister" (1994) before appearing in her second Hollywood production, Quentin Tarantino's aggressively hip crime film "Pulp Fiction" (1994). As boxer Bruce Willis' girlfriend, de Medeiros made a much softer and more endearing impression than Uma Thurman. (Willis described de Medeiros as "this little tulip in hell").