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Appendectomy and cigarette smoking have been suggested to reduce the chance of developing ulcerative colitis. A case-control study was undertaken to determine the relative incidence of appendectomy in patients with ulcerative colitis.This case-control study examined the incidence of appendectomy in patients with ulcerative colitis and patients attending an orthopedic outpatient clinic.Of 100 patients with ulcerative colitis, 75 pairs were matched for age, gender, and cigarette smoking. The ulcerative colitis group had an appendectomy rate of 8 percent (6/75), compared with 21 percent in the control group (P =0.018). The odds ratio was 3.5 (95 percent confidence interval, 1.15-10.6).No previous study has examined the effect of appendectomy, controlling for cigarette smoking. This study confirms that appendectomy protects against or reduces the chance of development of ulcerative colitis. A possible immunological explanation for this effect is advanced.