The divergent findings of hormone replacement therapy (HRT) from observational and randomized clinical studies are summarized and reasons for the different results are postulated. Chronic use of HRT since menopause has no harmful effects on CHD event rate, while the initiation of therapy after a recent cardiovascular event causes an early increase in recurrent CHD events. Once endothelial dysfunction and atherosclerotic disease has developed, the starting of HRT promotes plaque instability, vascular inflammation and prothrombotic effects. The timing of HRT use since menopause is therefore crucial in the effectiveness and safety of HRT on the vascular system.