We analyzed data from a population-based case-control study to investigate whether combined hormone replacement therapy influences the incidence of high-grade and -stage endometrial cancer. Subjects were women with epithelial endometrial cancer (N = 730) diagnosed during 1985-1991 and controls identified through random digit dialing (N = 1,002). Relative to hormone nonusers, women who took unopposed estrogens (mostly conjugated estrogens) for 3 or more years had a fivefold increase in the risk of tumors with myometrial invasion; the corresponding relative risk associated with combined therapy (estrogen and cyclic or continuous progestogen) for 3 or more years was only 1.3 (95% confidence interval = 0.8-2.2). We found a similar pattern of association for high-grade tumors.