We performed a case-control study of the effect of tobacco smoking on the risk of acquiring ulcerative colitis among the 304,000 members of a health maintenance organization. Smoking histories before the date of the onset of ulcerative colitis were compared in 212 cases and an equal number of controls matched for age and sex who were selected from the enrollment file of the health maintenance organization. The relative risk of ulcerative colitis among current cigarette smokers as compared with nonsmokers was 0.6 (95 percent confidence interval, 0.4 to 1.0); however, among former cigarette smokers it was 2.0 (95 percent confidence interval, 1.1 to 3.7). These values remained after adjustment for socioeconomic factors and for coffee and alcohol consumption. The higher risk among former smokers could not be explained by postulating that smokers gave up tobacco near the time of disease onset because of early symptoms of ulcerative colitis. The relative risk of ulcerative colitis among former smokers increased in proportion to the cumulative number of cigarettes smoked before the onset of disease, suggesting a causal relationship between this exposure and disease occurrence. No difference in risk was observed among current smokers according to cumulative amount smoked. We conclude that former and current tobacco use may have opposite effects on the risk of acquiring ulcerative colitis.