Obesity and menopausal estrogen therapy are established risk factors for endometrial cancer. However, the joint effects of obesity and menopausal hormone therapy on endometrial cancer risk are incompletely understood. We addressed this issue in a cohort of 103,882 women ages 50 to 71 years at baseline in 1995 to 1996. During a median of 4.6 years, which contributed to a total of 455,304 person-years of follow-up through 2000, 677 cases of endometrial cancer were ascertained. Both baseline body mass index (BMI) and adult weight gain were associated with increased endometrial cancer risk. The multivariate relative risk (RR) comparing obese with normal weight women (BMI >30 versus <25 kg/m(2)) was 3.03 [95% confidence interval (95% CI), 2.50-3.68]. Compared with women with stable weight (gained or lost <5 kg) between age 18 and baseline, women who gained >or=20 kg had a RR of 2.75 (95% CI, 1.96-3.86). Menopausal hormone therapy significantly modified the relations of BMI (P(interaction) < 0.001) and adult weight gain (P(interaction) = 0.004) to endometrial cancer risk. Compared with normal weight, the RRs for obesity were 5.41 (95% CI, 4.01-7.29) among women who never used menopausal hormone therapy, 2.53 (95% CI, 1.21-5.30) among former menopausal hormone therapy users, and 1.44 (95% CI, 1.00-2.05) among current users. Compared with a stable weight between age 18 and baseline, the RRs for weight gain of >or=20 kg among never users and ever users of menopausal hormone therapy were 5.35 (95% CI, 3.01-9.52) and 1.43 (95% CI, 0.96-2.15), respectively. We conclude that both current adiposity and adult weight gain are associated with substantial increases in the risk of endometrial cancer, with relations particularly evident among never users of menopausal hormone therapy.