An inverse association between smoking and endometrial cancer has generally been observed, primarily among current smokers. To assess this association, we analyzed data from the prospective Nurses' Health Study. From 1976 to 2000, 702 cases of invasive endometrial cancer were identified during 1.8 million person-years of follow-up. Smoking status was assessed in 1976 and updated every 2 years. Cox proportional hazards models were used to calculate multivariate relative risks (RRs), controlling for endometrial cancer risk factors. Compared to never smokers, the multivariate RR of endometrial cancer was significantly lower among both current smokers (RR = 0.63; 95% CI = 0.50-0.79) and past smokers (RR = 0.73; 95% CI = 0.62-0.87). When additionally adjusting for body mass index (BMI), the RR for current smokers was attenuated (RR = 0.72; 95% CI = 0.57-0.90), but the RR for past smokers did not change. Risk was lower among women who smoked 35 or more cigarettes a day (RR = 0.60; 95% CI = 0.39-0.91) and among those who smoked for 40 or more years (RR = 0.63; 95% CI = 0.45-0.87). Tests for trend, which excluded never smokers, were not statistically significant for any of the smoking variables analyzed. These data indicate that both current and past smoking are associated with a lower risk of endometrial cancer. The findings provide insight into disease etiology and suggest that the influence of smoking on endometrial cancer risk occurs even in early adulthood, is long-lasting, and may not be attributed solely to short-term hormonal modulation.