OBJECTIVE: The purpose of this study was to evaluate the acceptability and endometrial safety of a twice-weekly administration of transdermal estradiol (0.05 mg) systems and vaginal progesterone gel (Crinone [Serono, Rome, Italy] 4%, 45 mg/d) as a continuous combined nonoral hormone replacement therapy regimen. STUDY DESIGN: Thirty-five postmenopausal women took part in this 1-year prospective observational trial. The bleeding pattern, blood pressure, weight, endometrial thickness, and endometrial histologic characteristics of the women were monitored. Mean values were compared before and after treatment by paired Student t tests. RESULTS: Twenty-six (74.3%) women completed the study and were totally amenorrheic. A total of 350 cycles yielded valuable data. Of these, 287 (82%) cycles were amenorrheic. At month 3, blood pressure and weight decreased significantly. At final assessment, endometrial thickness was significantly greater than baseline (4.6 +/- 0.9 vs 3.6 +/- 0.9 mm; P <.0005), and histologic examination revealed endometrial atrophy in 24 (92.3%) cases and signs of decidualization in 2 cases. CONCLUSION: Transdermal estradiol and a twice-weekly administration of the vaginal progesterone gel Crinone constitutes a new, viable hormone replacement therapy regimen. It represents a practical option for a no-bleed treatment, ensuring both high endometrial protection and the inherent safety linked to administrating physiologic hormones nonorally.