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- Nicolas Cage as Benjamin Franklin "Ben" Gates
- Justin Bartha as Riley Poole
- Diane Kruger as Dr. Abigail Chase
- Jon Voight as Patrick Henry Gates
- Helen Mirren as Dr. Emily Appleton
- Ed Harris as Mitch Wilkinson
- Harvey Keitel as Special Agent Sadusky
- Armando Riesco as Special Agent Hendricks
- Alicia Coppola as Special Agent Spellman
- Albert Hall as Dr. Nichols
- Bruce Greenwood as President of the United States
- Ty Burrell as Connor