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.