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Peter O'Brien portrayed John Howlett in X-Men Origins: Wolverine.

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In the 1980s, Peter ventured into acting scoring a role in Australian television drama series. He played a regular role in short-lived soap operaStarting Out (1983), and had a guest role in Carson's Law (1983) followed by a brief appearance in Prisoner in 1984. He appeared in the The Henderson Kids. He was later a regular original cast member of soap Neighbours which began in 1985. As Shane Ramsay, he became one of the serial's most popular cast members, continuing in the series until 1987. He later played a leading regular role in drama series The Flying Doctors from 1988 until 1991.

More recently, he starred in television series Queer as Folk, White Collar Blue, Hell Has Harbour Views and Gossip Girl.

O'Brien has appeared in numerous mini-series, including The Day of the Roses and Through My Eyes (the story of Lindy Chamberlain). He has also guest starred on numerous television series, including Halifax f.p.. For his work, O'Brien has won Australian Film Institute and Logie Awards. He also appeared as Carl Morgan in Spellbinder 2: Land of the Dragon Lord, and he appeared in the 1998 Australian/Brisbane comedy television series of Minty. In 2009 he played Sydney underworld figure and racing identity George Freeman in the series Underbelly: A Tale of Two Cities.

O'Brien was recently part of the cast of BBC Television series Casualty as a new consultant called Stitch. He made his debut on 18 March 2007. He has also appeared in ITV1s cop show The Bill in which he played Detective Inspector Peter Kavanaugh, a corrupt officer who seduces Detective Sergeant Samantha Nixon to gain information for the criminals he works for.

He appeared as Ed in "The Waters of Mars", the second of the 2009 specials of Doctor Who.

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