We conducted a case-control study of the protective effect of appendectomy on the development of ulcerative colitis. We calculated the risk of ulcerative colitis in 716 incident cases of ulcerative colitis and 2,747 controls according to appendectomy status, using data from the United Kingdom General Practice Research Database. We also studied a random sample of 100 cases and 100 controls to validate the subject's history of appendectomy. Fifteen cases (2%) and 109 (4%) controls had a computer-recorded history of appendectomy [odds ratio (OR) = 0.5; 95% confidence interval (CI) = 0.3-0.9]. In the sample, the OR was 0.3 (95% CI = 0.1-0.9). Appendectomy appears to protect against ulcerative colitis.