The endometrial response to oral, cyclic conjugated equine estrogens with and without the randomized addition of medroxyprogesterone acetate was evaluated in 95 postmenopausal women with respect to morphology and bleeding patterns. At 1 year, therapy with 0.625 mg conjugated equine estrogens or 1.25 mg conjugated equine estrogens for 25 days of a 30-day cycle and 5 mg medroxyprogesterone acetate added to the last 11 days of the conjugated equine estrogens cycle was associated with hyperplasia in 0 and 10% of the patients, respectively (P = not significant). Hyperplasia developed in 30 and 57% of the patients who received the above conjugated equine estrogens and placebo regimens, respectively. Irregular, breakthrough bleeding occurred in 14% of the conjugated equine estrogens/medroxyprogesterone acetate users and in 54% of the conjugated equine estrogens/placebo users. The results of this study indicate that 1 year of therapy with 0.625 mg conjugated equine estrogens and 5 mg medroxyprogesterone acetate provided the most satisfactory endometrial protection against hyperplasia and was associated with relatively low rates of breakthrough bleeding.