OBJECTIVE To reconcile apparently conflicting evidence regarding the use of hormone therapy as a health-preserving strategy in postmenopausal women in light of that fact that findings from animal studies, human observation studies, and human clinical trials are consistent for outcomes such as fracture and breast cancer but differ for coronary heart disease (CHD). METHODS Literature review and generation of a unified hypothesis consistent with all of the data. METHODS Animal trials, human observational studies, human studies of biologic intermediates, and human clinical trials. METHODS Premenopausal and postmenopausal women with or without antecedent CHD. METHODS Coronary heart disease events, proxies, risk factors, and related mechanisms. RESULTS The complex CHD responses to hormone therapy in recent human trials likely reflect a combination of [1] early erosion/rupture of "vulnerable" coronary plaque, which is made worse by hormone therapy, [2] long-term reduction in plaque formation, which is improved by hormone therapy, and [3] modulation of the vasculoprotective actions of estrogens by systemic progestogens. CONCLUSIONS The unified hypothesis predicts that hormone therapy initiated at the time of menopause should produce a decrease in CHD over time. In contrast, hormone therapy begun years after menopause should produce an increase in CHD events shortly after therapy is begun, followed later by benefit. In women who require progestogens for endometrial protection, there should be greater CHD benefit from use of progestogens with less systemic activity. The unified hypothesis is consistent both with plausible biologic mechanisms and with evidence from animal studies, human observational studies, and human clinical trials such as the Women's Health Initiative. In the absence of evidence from human trials that specifically involve initiation of hormone therapy in perimenopausal women, practitioners and patients can use the unified hypothesis as a rational tool to guide decisions about clinical management.