BACKGROUND/AIMS: Defining risk factors for ulcerative colitis (UC) is important to better understand the pathogenesis of this idiopathic disease. One factor modulating the disease is smoking. A pilot study showed the absence of appendectomy in the medical history of patients with ulcerative colitis. The aim of the present case control study was to compare the relative risk of developing UC after appendectomy with the relative risk of developing UC with an intact appendix. METHODS: One hundred seventy-four (84 females and 90 males, mean age 34.9 years) consecutive UC patients examined at our inflammatory bowel disease clinic or hospital ward, were included. Fifty-six had pancolitis (32%) and 118 (68%) suffered from left-sided colitis. The control group consisted of 161 consecutive patients examined at the orthopedic clinic (86 females and 75 males, mean age 40.9 years). RESULTS: Two parameters, absence of appendectomy and smoking, were closely related to the development of UC. Before the onset of UC, only 1 of the 174 patients (0.6%) had undergone an appendectomy. Of the 161 controls, 41 (25.4%) had undergone an appendectomy. The difference between the two groups was highly significant with an odds ratio of 59.1 (95% CI, 18-189; P < 0.001). The relative risk of getting the disease associated with nonsmoking was 2.95 (95% CI, 1.69-5.17). CONCLUSIONS: Appendectomy is a protective factor against UC.