A case of a patient with a malignant thymoma who developed an unusual form of colitis is reported. The patient was a previously healthy 20-year-old man who was referred to the Johns Hopkins Medical Institution for biopsy and resection of a mediastinal mass, which proved to be a malignant thymoma. During this hospitalization and subsequently, the patient developed severe chronic diarrhea, the etiology of which remained uncertain after routine work-up, including cultures. Colonoscopic biopsies revealed only minimal inflammation but numerous, prominent apoptotic lesions within crypt epithelium, suggestive of an autoimmune or graft-versus-host-like colitis. The patient, who was immunocompetent and human immunodeficiency virus (HIV) negative, had no known risk factors for graft-versus-host-disease (e.g., no blood transfusions, no transplantation history before diarrheal episodes). Stool cultures for pathogenic bacteria and viruses were negative. The diarrhea and histologic findings eventually improved with steroid therapy yet returned on recurrence of the thymoma. This unusual form of colitis has not been previously reported to be associated with thymoma and is interesting in light of the role the thymus plays in immune regulation.