Despite biologically plausible mechanisms of benefit and data from observational studies suggesting cardioprotection from menopausal hormone therapy, the results of randomized clinical trials in both healthy women and women with established coronary heart disease failed to show benefit and indeed imparted some harm. In 2009, menopausal hormone therapy is not indicated for the primary prevention of coronary heart disease or of cardiovascular disease. Prevention of cardiovascular disease in women should be addressed by the aggressive identification and modification of established cardiovascular risk factors. Much remains unknown about the mechanisms of menopausal hormone therapy action and the issue of whether there is a therapeutic window of opportunity for its use.Keywords Hormone Therapy . Estrogen . Cardiovascular Protection . Clinical Trials Epidemiologic data [1] have demonstrated an association between postmenopausal estrogen use and reduction in the risk of coronary heart disease, postulated as mediated by a favorable effect of estrogen on traditional coronary risk factors [2]. Biologically plausible mechanisms for cardioprotection include favorable lipid effects; favorable effects on coagulation, fibrinolysis, and homocysteine; decreased inflammatory response to atherosclerosis; decreased vascular smooth muscle proliferation; promotion of endotheliumdependent vascular dilation and decreased thrombosis; lessened LDL oxidation; and promotion of angiogenesis, among others. But biologic plausibility alone is insufficient evidence for cardioprotection. Why, then, have randomized clinical trials of menopausal hormone therapy failed to show benefit and indeed imparted harm? Hormone users in the observational studies tended to be healthier, wealthier, and have fewer coronary risk characteristics. A 2002 systematic review and meta-analysis of menopausal hormone therapy for the primary prevention of cardiovascular disease displayed that adjustment of these observational studies for socioeconomic status, educational level, and major coronary risk factors failed to support the use of such therapy for the primary prevention of cardiovascular and coronary heart disease [3].What data derive from the major randomized clinical trials? The Heart and Estrogen/Progestin Replacement Study (HERS) allocated 2,763 menopausal women with a uterus and with documented coronary heart disease to 0.625 mg oral conjugated estrogen (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA) daily vs. placebo. The primary outcome was the combined endpoint of nonfatal myocardial infarction or coronary death. Surveillance at 6.8 years in HERS and HERS II [4,5] showed no reduction in the primary endpoint or in the risk of cardiovascular events but a pattern of early increased risk of coronary events. Adverse events included an increased risk of venous thromboembolism and of biliary tract surgery without significant effect on breast cancer, any cancer, hip fracture, or any fracture. The HERS investigators concluded that