Numerous evidence have suggested a physiologic action of sexual steroids upon the cardiovascular system and the coherence of epidemiological studies have raised the possibility of a positive action of estradiol in preventing cardiovascular disease, specially through atheroma inhibition and other vascular wall-related mechanisms. From an experimental point of view, some clinical trials have demonstrated an improvement in some intermediate clinical variables, such as hypercholesterolemia and hypertension, after the administration of estradiol. Nonetheless, the HERS study, the first secondary prevention trial of estrogen and cardiovascular disease, failed to demonstrate these positive actions suggested by epidemiological studies and the efficacy of estradiol in the treatment of postmenopausal women with cardiovascular disease has been questioned. In spite of this, the HERS study has also been questioned because of different pitfalls in its development and, for some authors, it is inconclusive. Therefore, at present, it is not possible to make an evidence based clinical decision regarding the key question about the real actions of estradiol in the prevention of cardiovascular disease in postmenopausal women.