OBJECTIVE: To assess the tolerability and endometrial effects of vaginal administration of an allopregnanolone gel to postmenopausal women undergoing estrogen therapy. METHODS: Thirteen postmenopausal women included in the study were divided into two groups and submitted to two consecutive cycles of 28 days during which they received 2 mg oral estradiol valerate daily and vaginally administered allopregnanolone gel during the last 10 days of the second cycle (group 1) or during the last 10 days of each cycle (group 2). Systemic adverse effects, vaginal bleeding and endometrial histology were characterized, with group 1 patients being submitted to two endometrial biopsies (days 28 and 56) and group 2 patients to one biopsy (day 56). RESULTS: Five patients did not show any adverse effect. Mastalgia was the most frequently reported adverse effect (four cases), followed by headache and abdominal pain (two cases each). The adverse effects were mild and did not interfere with the adequate use of the medication prescribed. Vaginal bleeding due to deprivation was observed in three of the seven patients submitted to one treatment cycle with allopregnanolone (group 1) and in two of six patients submitted to two treatment cycles (group 2). Endometrial biopsy findings did not suggest any secretory action after exposure to allopregnanolone. CONCLUSIONS: Tolerability of vaginal administration of allopregnanolone gel was good. Studies employing a larger series and longer time of follow-up are necessary to determine the endometrial effects of this drug.