BACKGROUND We sought to evaluate the long-term safety and efficacy of cyclic combined estradiol valerate and cyproterone acetate. METHODS A six-year, single center, open study was performed of forty-eight recently postmenopausal women. We evaluated biochemical markers of bone turnover, bone mineral content, bone mineral density, serum lipids, climacteric symptoms, and bleeding throughout the six-year period. Ultrasound evaluation of the endometrium was performed yearly for the first two years. RESULTS Markers of bone turnover were decreased over the study period, while bone mineral content and density remained unchanged. High density lipoprotein cholesterol levels were increased with unchanged blood pressure over the six years. Menopausal symptoms showed significant improvements within 6 months. Endometrial scan results never required hysteroscopic evaluation. CONCLUSIONS Sequentially combined estradiol valerate and cyproterone acetate can be used for an indefinite number of years in women with recent natural menopause. Cyproterone acetate provides adequate endometrial protection and cycle control while allowing estradiol valerate to exert its positive effects on lipid profile, bone metabolism, and climacteric symptoms.