Estrogen-alone therapy (ET) or estrogen and progestin (EPT) as menopausal hormone therapy (HT) has been commonly used to alleviate menopausal symptoms. Treatments containing > or = 10 days per month of progestin are considered relatively safe with respect to endometrial cancer risk. However, the endometrial safety of long-term EPT regimens is uncertain. We conducted a case-control study of 311 invasive endometrial cancer cases and 570 controls nested within the California Teachers Study cohort. We used unconditional logistic regression to obtain odds ratios (OR) and 95% confidence intervals (95% CI) for the association between long-term HT use and endometrial cancer risk, and to assess the modifying effect of body mass index (BMI). Long-term (> or = 10 years) use of ET, sequential EPT with <10 days per month progestin, and continuous-combined EPT (> or = 25 days/month progestin) were all associated with an elevated risk of endometrial cancer (OR, 4.5; 95% CI, 2.5-8.1; OR, 4.4; 95% CI, 1.7-11.2; and OR, 2.1; 95% CI, 1.3-3.3, respectively; all P(trend) < 0.001). The risk associated with short-term use was elevated only for ET preparations. The association for continuous-combined EPT was confined to thinner women (BMI, <25 kg/m2; P(interaction) = 0.03). Among heavier women (BMI, > or = 25 kg/m2), use of continuous-combined EPT was associated with a statistically nonsignificant reduction in risk. These findings confirm that long-term use of ET, sequential EPT, or, among normal weight women, continuous-combined EPT is associated with increased risk of endometrial cancer.