Endometrial cancer is a disease primarily driven by cumulative exposure to estrogen unopposed by progesterone. Reproductive factors associated with changes in endogenous hormone levels and use of exogenous hormones such as postmenopausal hormones influence the risk of disease. The authors used the Nurses' Health Study, comprised of 121,700 nurses, to assess the above associations. Over 28 years of follow-up, 778 adenocarcinoma cases were diagnosed and 1,850,078 person-years were accumulated. Cox proportional hazards models were used to estimate relative risks (RR) and 95% confidence intervals (CI). A late age at menarche decreased the risk independent of body mass index (BMI) (P-trend = 0.02). A late age at menopause increased cancer risk (P-trend = 0.0003). An advanced age at last birth reduced the risk (P-trend < 0.0001), however, an inverse association with age at first birth and parity diminished after adjustment for age at last birth. Compared with never users, an increased risk was observed among long-term (> or =5 years) users of both estrogen (E) (RR = 7.67, 95% CI: 5.57, 10.57) and combined estrogen plus progesterone (E+P) (RR = 1.52, 95% CI: 1.03, 2.23). Normal-weight (BMI < 25) women had the highest risk following E or E+P use (P-interaction-E = 0.0008, P-interaction-E+P = 0.02). The findings from this study underscore the importance of hormonal mechanisms in endometrial carcinogenesis.