Estrogen therapy reduces the risk of osteoporosis and cardiovascular diseases but is associated with an increased risk of endometrial cancer. We have assessed the impact of a regimen of estrogen with progestogen on risk of endometrial cancer for women 48 years and older. We conducted a case-control study in Ontario, Canada, from 1994 to 1998 by interviewing registry-based cases (n = 512) and population controls (n = 513) to obtain information on use of hormones and dietary habits. Compared to non-users, the use of opposed hormone therapy in sequential regimen for more than three years showed a borderline increase in risk (OR = 1.49, 95% CI 0.93-2. 40), but this increase was much less than among women on unopposed estrogen (OR = 4.12, 95% CI 2.21-7.71). Stronger associations were observed when duration of sequential hormone use was examined as a continuous variable (OR per three years of use = 1.21, 95% CI 1.03-1. 42). The effect of opposed hormone therapy on endometrial cancer risk appears to vary both by usage patterns and by patient characteristics of body weight and history of diabetes.