A myriad of the retrospective studies have shown the benefit of hormone replacement therapy (HRT) on cardiovascular disease. It has been consistently shown that estrogen decreases total and LDL cholesterol, but increases the HDL cholesterol, resulting in a favorable cardiovascular outcome. In addition, it has been reported that estrogen has a beneficial role toward vascular function. The benefit of HRT on cardiovascular disease did not become a matter for suspicion or skepticism until the arrival of primary and secondary prevention clinical trial data. A large body of evidence from secondary prevention trials, such as HERS, EVA and WAVE, revealed that HRT has no beneficial effect at all toward cardiovascular disease protection; conversely, it was revealed to even be harmful. HRT increased the risk of CHD, DVT and strokes, as well as of cancers in postmenopausal women with CHD, with the worst evidence coming from a primary prevention trial. The Women's Health Initiative (WHI) study, the largest of the HRT trials, revealed the same findings as those of secondary prevention trials. In this trial, HRT significantly increased the risks of CHD, DVT, strokes and cancers, further confirming the previous findings. The lack of benefit of HRT in those trials can not be explained by the beneficial influence of HRT on the lipid profile and vascular function. Many researchers that still regard HRT as cardioprotective argue that the route, combination of drugs or even the dose of the drug administered would make differences. However, it is the increased VLDL synthesis and risk of thrombosis that make HRT harmful. HRT increase, VLDL synthesis that results in the generation of atherogenic small dense LDL and thrombus formation. In addition, HRT increases the risk of thrombosis by activating the coagulation pathway independently of VLDL synthesis. It has been reported that transdermal estrogen therapy does not increase VLDL synthesis or thrombus formation, being allegedly beneficial. However, it should not be forgotten that even the present data is not decisive and not confirmative for performing another new clinical trial of HRT being potentially harmful