Crohn's disease is a chronic disease of unknown etiology. Previous reports have suggested that cigarette smoking may be associated with the development of Crohn's disease. To examine this association, we conducted a case-control study of patients referred to a single practice over a 7-month period. The cigarette-smoking habits of 115 patients with Crohn's disease were compared with the cigarette-smoking exposure of 109 patients with the irritable bowel syndrome. Patients with Crohn's disease were more likely to smoke at the time of symptom onset than were irritable bowel syndrome controls (age and sex adjusted odds ratio 3.71, 95% confidence interval 1.93-7.13). After the diagnosis of Crohn's disease, patients were less likely to quit smoking (odds ratio 0.35, 95% confidence interval 0.18-0.69) than controls. This study demonstrates an association and a temporal relationship between cigarette smoking and Crohn's disease. For the exposure to be considered an etiologic factor for disease, biologic plausibility and pathophysiologic mechanisms require elucidation.