The film begins with the antagonist, Dr. Heiter (Dieter Laser), kidnapping a truck driver by the side of a road. Later, two U.S. tourists, Lindsay (Ashley C. Williams) and Jenny (Ashlynn Yennie), arrive at Heiter's house as they search for help after getting a flat tire. Heiter quickly drugs the women, when they awake they find themselves beside the kidnapped trucker in a makeshift hospital ward in the doctor's basement. Heiter informs the trucker that he is not a 'match' for the girls and kills him. When the women next wake, the trucker has been replaced by a new captive, Japanese tourist Katsuro (Akihiro Kitamura).