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- Roy Scheider as Dr. Heywood R. Floyd
- John Lithgow as Dr. Walter Curnow
- Helen Mirren as Tanya Kirbuk
- Bob Balaban as Dr. R. Chandra
- Keir Dullea as Dave Bowman
- Douglas Rain as HAL 9000 (voice)
- Madolyn Smith as Caroline Floyd
- Saveliy Kramarov as Dr. Vladimir Rudenko
- Taliesin Jaffe as Christopher Floyd
- James McEachin as Victor Milson
- Mary Jo Deschanel as Betty Fernandez
- Elya Baskin as Maxim Brajlovsky
- Dana Elcar as Dimitri Moiseyevich
- Oleg Rudnik as Dr. Vasili Orlov
- Natasha Shneider as Irina Yakunina
- Vladimir Skomarovsky as Yuri Svetlanov
- Victor Steinbach as Nikolaj Ternovsky
- Candice Bergen as SAL 9000 (voice)