Whereas observational data for postmenopausal women using hormone therapy (HT) have shown a protective effect against cardiovascular disease, prospective, randomized trials have demonstrated a harmful effect on the vascular system. This study describes the effects of HT on lipids, hemostatic parameters, inflammation, and the vascular wall. Reasons for the different results of observational and experimental studies of HT are postulated. The timing of hormonal supplementation seems crucial. Used chronically, HT has no harmful effects; however, first-time use of HT after a recent cardiovascular event results in an early increase in adverse cardiovascular events. In most observational studies, women started HT for postmenopausal symptoms, whereas in experimental studies, women started HT 10 to 20 years or longer after menopause. Cumulative evidence supports the hypothesis that HT has more effect in maintaining vascular health than in alleviating endothelial dysfunction. HT has not proven beneficial in the long term in women at risk of a cardiovascular event. The interval between menopause and the start of HT plays a crucial role in the effectiveness of HT in the vascular system.