OBJECTIVE:This review critiques The Women's Health Initiative (WHI) study, focusing on aspects of the study design contributing to the adverse events resulting in the study's discontinuation. CONCLUSION(S):Two aspects of the design contributed to the adverse events: [1] The decision to administer continuous combined conjugated equine estrogen (CEE)/medroxyprogesterone acetate (MPA) or E alone as a standard regimen to a population with little previous hormonal treatment, ranging in age from 50-79 years, who, because of their age, were predisposed to coronary and cerebral atherosclerosis. [2] Selection of an untested regimen of continuous combined CEE plus MPA, which we hypothesize, negated the protective effect of E on the cardiovascular and cerebrovascular systems. Multiple observational studies that preceded the WHI study concluded that the use of E alone and E plus cyclic (not daily) progestin combination treatments initiated in early menopause had beneficial effects. The therapeutic regimens resulted in prevention of atherosclerosis and reductions in coronary artery disease mortality. It is our conclusion that the WHI hormonal replacement study had major design flaws that led to adverse conclusions about the positive effects of hormone therapy. An alternative hormonal regimen is proposed that, on the basis of data supporting its beneficial cardiovascular effects, when initiated appropriately in a population of younger, more recently menopausal women, has promise to yield a more favorable risk/benefit outcome.