The long-held belief that outcome data from intervention trials in men are generalizable to women has created the framework in which the primary prevention of coronary heart disease (CHD) in women is viewed, but over the past decade, data have accumulated to refute such a supposition of generalizability. These lines of evidence concern the sex-specific efficacy of CHD primary prevention therapies and timing of postmenopausal hormone replacement therapy (HRT) initiation according to age and time since menopause as modifiers of efficacy and risk. Although the standard primary prevention therapies of statins and aspirin reduce CHD in men, neither therapy reduces CHD and, more importantly, mortality in women under primary prevention conditions. Nonetheless, HRT significantly reduces CHD and mortality in primary prevention when it is initiated in women who are younger than 60 or are less than 10 years since menopause. Herein, the efficacy of the commonly used therapies for the primary prevention of CHD in women, statins, aspirin, and postmenopausal HRT is discussed. The comparative risks of these therapies will be discussed in Part 2 of this series.