To examine the relationship between exogenous estrogen administration and endometrial cancer, we used data from the Cancer and Steroid Hormone Study, a multicenter, population-based case-control study. Estrogen replacement therapy for greater than or equal to 2 years was associated with an increased risk of both localized and extrauterine cancer (relative risk = 2.8, 95% confidence limits 1.6, 4.6; relative risk = 2.9, 95% confidence limits 0.9, 9.4, respectively). However, the latter finding was based on a small number of cases in which estrogen was used. Women who underwent estrogen replacement therapy for greater than or equal to 2 years had significantly elevated risks of endometrial cancer (2.1 for 2 to 5 years and 3.5 for greater than or equal to 6 years). An elevated risk persisted for greater than or equal to 6 years after discontinuation of therapy. Women who exclusively used conjugated equine estrogen preparations less than or equal to 0.625 mg had no increased risk of endometrial cancer. A history of oral contraceptive use appeared to reduce the risk of endometrial cancer associated with estrogen replacement therapy. However, these latter two potentially important findings were based on a small number of cases in which hormones were used.