To determine the relationship between cigarette smoking and endometrial cancer, we conducted a case-control study. The cases were 726 patients with histologically confirmed endometrial cancers 74 years of age or less (median age, 59 years; range, 31-74) admitted between 1983 and 1992 to the Ospedale Maggiore (including the four largest teaching and general hospitals in the greater Milan area), to the Obstetrics and Gynecology University Clinics, and to the National Cancer Institute of Milan. The controls were 1452 patients younger than 75 years (median age, 59; range, 25-74) admitted for acute, nongynecological, nonhormonal, nonneoplastic conditions to the same network of hospitals where cases had been identified. Cases were less frequently ever-smokers (19%) than controls (25%). In comparison with never-smokers, the relative risk (RR) of endometrial cancer was 0.8 (95% confidence interval, CI, 0.7-1.1) in current smokers and 0.6 (95% CI 0.4-0.9) in ex-smokers. The risk of endometrial cancer decreased with number of cigarettes smoked per day and duration of habit. The estimated RR were, in comparison with never-smokers, 0.8 and 0.6 respectively in smokers of less than 20 and 20 or more cigarettes per day (chi 2(1) trend 5.48, P = 0.02) and 1.0 and 0.5 in ever-smokers for less than 20 and for 20 years or more. There was no clear relation with time since first smoking, but the RR was lower in ex-smokers who had stopped smoking less than 10 years before the interview (RR, 0.4; 95% CI, 0.2-0.8) than in those who had stopped 10 years or more before (RR, 0.8; 95% CI, 0.5-1.4). The estimated RR for ever-smokers was close to unity in premenopausal women, but apparently stronger in premenopause. Likewise the RR was 0.9 in lean (< 25 Quetelet's index) smoking women in comparison with lean nonsmokers, but smoking appeared to reduce the association with overweight. The estimated RR of endometrial cancer, in comparison with nonsmokers with Quetelet's index < 25 was 2.0 in nonsmokers with Quetelet's index > or = 25, and 1.3 in smokers with Quetelet's index > or = 25. These findings confirm the role of smoking on endometrial cancer risk. The risk reduction is, however, moderate in relative terms, and negligible from a public health point of view, in consideration of the negative consequences of smoking in several other diseases.