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- Famke Janssen as Jean Grey / Dark Phoenix: A former member of the X-Men, upon being resurrected, Grey gives in to her alternate personality, the Phoenix, an aggressive Class 5 mutant who possesses potentially limitless telepathic and telekinetic powers. Her mutant powers rival those of Xavier.
- Shawn Ashmore as Bobby Drake / Iceman: A young mutant, Iceman can create constructs of ice or blasts of cold.
- Patrick Stewart as Charles Xavier / Professor X: The founder of the Xavier's Institute for Gifted Mutants and a mutant with uncharted telepathic powers, Xavier is an authority on genetic mutation and an advocate of peaceful relations between human and mutant kind.
- Ian McKellen as Erik Lehnsherr / Magneto: Leader and founder of the Brotherhood, Magneto is a Holocaust survivor who wages war against humanity in the name of mutant superiority. He has the ability to control and manipulate metal, making him one of the most powerful mutants.
- Anna Paquin as Marie / Rogue: A young mutant woman from the Deep South whose power causes her to temporarily take on the powers of anyone she touches, leaving her victims unconscious, Rogue's lack of control over her power causes a great deal of strain on her relationship with Iceman.
- Kelsey Grammer as Dr. Hank McCoy / Beast: A former student of Xavier's Institute for Gifted Mutants who is now a member of the U.S. Cabinet as the Secretary of Mutant Affairs, Beast is a brilliant scientist and statesman. He is covered in blue fur and has heightened strength and agility, as well as pointed fangs and a lion-like roar.
- James Marsden as Scott Summers / Cyclops: The X-Men's field leader, Cyclops emits powerful energy blasts from his eyes, and must wear specially made glasses to prevent the destruction of anything he looks at. Although he is in a committed relationship with Jean Grey, her Phoenix persona kills him early in the film.
- Rebecca Romijn as Raven / Mystique: Magneto's blue-skinned right-hand woman possesses the ability to shape-shift to mimic anyone's appearance, as well as fight with incredible agility and strength. She jumps in front of cure darts intended for Magneto and, after she loses her mutant abilities as a result, Magneto abandons her.
- Aaron Stanford as John Allerdyce / Pyro: A former student of Xavier's School for Gifted Mutants with a grudge against his former friend Bobby Drake, Pyro has the ability to manipulate fire, generated through wrist-mounted lighters.
- Vinnie Jones as Cain Marko / Juggernaut: A criminal recruited by the Brotherhood in a prison truck, Juggernaut is incredibly strong, fast and, once he gains momentum, he is nearly unstoppable.