Cardiovascular protection of hormonal replacement therapy was considered a fact. The effects of estrogens on lipid levels and vascular health gave biological support to estrogen cardioprotection. The recently published HERS study showing no protective effects of estrogen and progesterone replacement therapy on the risk of myocardial infarction or coronary deaths is provoking perplexity. These surprising results may have several causes such as the use of progesterone, the associated use of cardioprotective agents or the short observation period. However, the study results scope is restricted to secondary prevention. These cannot be extrapolated to frequent conditions of postmenopausal women such as primary prevention or sequential schemes. Likewise, this investigation underscores the importance of a critical and continued evaluation of apparently well established therapeutic approaches.