In film, he is best known for playing Daniel Barenboim and Álvaro de la Quadra in the biographical dramas Hilary and Jackie and Elizabeth, respectively (both 1998), Bassianus in the Shakespeare adaptation Titus (1999), and Gérard de Villefort in the historical drama The Count of Monte Cristo (2002).

James Frain was born in Leeds, West Riding of Yorkshire, and brought up in Stansted Mountfitchet, near Bishop's Stortford, Essex, the eldest of eight children of a teacher mother and a stockbroker father.

He played Thomas Cromwell in Showtime's The Tudors; the villainous billionaire "Chess" in the NBC superhero/crime drama series The Cape; heroic Templar Sir Gregory in the Syfy original film Dark Relic (2010); and vampire Franklin Mott in the HBO drama True Blood.

In season 2 of Grimm, Frain joined the cast as a mysterious recurring character named Eric Renard.

He was a recipient of the 2008 Drama Desk Award for Outstanding Ensemble Performances along with the rest of the cast of The Homecoming (2007).