There is some controversy about the prevalence of appendectomy and tonsillectomy among patients with Crohn's disease and a lower rate of appendectomy among patients with ulcerative colitis (UC). The objective of this study was to elucidate the role of appendectomy and tonsillectomy in Iranian patients with inflammatory bowel disease (IBD). Three hundred and eighty-two consecutive cases of UC and 46 cases of CD were included. Age and sex-matched controls were randomly selected. A total of 382 controls for UC and 184 controls for CD were enrolled. A standard record concerning smoking habit, history of appendectomy and tonsillectomy, OCP, and NSAID use was completed. Logistic regression analysis was used to evaluate potential confounding variables. Twelve patients (3.1%) with UC reported a previous history of appendectomy compared with 30 controls (7.9%) (OR=0.38, 95%CI=0.19-0.76, P<0.004). Appendectomy was reported by five patients (10.9%) with CD compared with four controls (2.2%) (OR=5.49, 95%CI=1.41-21.34, P<0.02). The logistic regression analysis showed that appendectomy is a risk factor in CD but has a modest protective effect for development of UC. No association with tonsillectomy was found for either disease. A statistically significant protective effect for smoking in UC was found (OR=0.2, 95%CI=0.13-0.32, P<0.0001). We have found an inverse association between OCP and NSAID use with UC, but not CD (P<0.0001 and P<0.001, respectively). Appendectomy is protective in UC, but a risk factor in CD among Iranian population. Tonsillectomy was not associated with either UC or CD disease. UC, but not CD, is a disease of non-smokers. The inverse association between ulcerative colitis and OCP or NSAID in the Iranian population is noted.