Previous studies of the association between cigarette smoking and endometrial cancer have yielded inconsistent results. There is some evidence that this discrepancy may be explained by differences in menopausal status between the groups of women studied. We addressed the issue of the effects of postmenopausal smoking on endometrial cancer risk using data from the Cancer and Steroid Hormone Study, a multicenter, population-based, case-control study of gynecologic cancers in the United States. We found that smoking after natural menopause is associated with a 70% reduced risk of endometrial cancer among estrogen users and a 50% reduced risk among nonusers of estrogen. These findings are consistent with previously proposed biologic effects of smoking on estrogen metabolism, which may have important clinical implications.