To examine the relationship between endometrial cancer and use of specific oral contraceptive (OC) formulations, we used data from the Cancer and Steroid Hormone Study, a multicenter, population-based, case-control study. Cases were 433 women aged 20 to 54 years with histologically confirmed epithelial endometrial cancer ascertained through six population-based cancer registries. Controls were 3191 women selected at random from the populations of these areas. Women who had used combination OCs for at least 12 months had an age-adjusted risk of developing endometrial cancer of 0.6 relative to those women who had never used OCs (95% confidence interval, 0.3 to 0.9). This protective effect persisted for at least 15 years after the cessation of OC use. Examination of the eight most frequently used OC formulations revealed little difference in the age-adjusted risks, which ranged from 0.2 to 0.7 for women who had ever used a formulation compared with women who had never used OCs. Use of OCs for 12 months or longer conferred protection against all three major histologic subtypes of endometrial cancer.