They have separated after five years of marriage, publicist Lewis Kay said Monday.
"The split is amicable and they have asked that the media please respect their privacy regarding this situation during this difficult time," Kay said.
The spokesman said the couple had no further comment.
Stamos, 40, and Romijn, 31, met in 1994 at a Victoria's Secret fashion show and began dating two months later. They married in September 1998.
The actress appeared in "X-Men," "X2: X-Men United," "Femme Fatale" and "Rollerball." Her upcoming films include "The Punisher" and "Godsend."
Stamos, best-known for his role as Jesse in the TV sitcom "Full House" from 1987 to 1995, played John Sears in last year's cable TV movie "The Reagans." In recent years, he's played on the Broadway stage.
Conan you got married too soon ... you missed your shot