Over the past decade, two informative events in primary prevention of coronary heart disease (CHD) have occurred for women's health. The first concerns hormone replacement therapy (HRT) where data have come full circle from presumed harm to consistency with observational data that HRT initiation in close proximity to menopause significantly reduces CHD and overall mortality. The other concerns sex-specific efficacy of CHD primary prevention therapies where lipid-lowering and aspirin therapy have not been conclusively shown to significantly reduce CHD and, more importantly, where there is lack of evidence that either therapy reduces overall mortality in women. Cumulated data support a 'window-of-opportunity' for maximal reduction of CHD and overall mortality and minimization of risks with HRT initiation before 60 years of age and/or within 10 years of menopause and continued for 6 years or more. There is a substantial increase in quality-adjusted life-years over a 5-30-year period in women who initiate HRT in close proximity to menopause, supporting HRT as a highly cost-effective strategy for improving quality-adjusted life. Although primary prevention therapies and HRT contrast in their efficacy to significantly reduce CHD and especially overall mortality in postmenopausal women, the magnitude and types of risks associated with HRT are similar to those associated with other medications commonly used in women's health. The cumulated data highlight the importance of studying the HRT cardioprotective hypothesis in women representative of those from whom the hypothesis was generated.