Although Clostridium difficile colitis is a common problem during chemotherapy, fulminant expression is rarely observed. Here, we describe a 68-year-old woman who developed fatal colitis due to Clostridium difficile infection. The patient was treated with CHOP therapy for relapsed lymphoma. In the nadir phase, she developed severe bloody diarrhea with a high fever and died within 12 hours after the beginning of symptoms. Clostridium difficile was identified in her stool and an autopsy showed hemorrhagic necrosis on the whole colon and rectum. This case demonstrates the substantial incidence of an unexpected feature with Clostridium difficile infection even with popular chemotherapy.