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Atherosclerosis is a chronic systemic inflammatory disease of the vasculature that accounts for the majority of morbidity and mortality in women. The incidence of atherosclerosis is low in premenopausal women and increases after ovariectomy. Experimental studies demonstrate inhibitory effects of natural estrogens on the progression of atherosclerosis. In contrast, results from recent hormone replacement trials using conjugated equine estrogens and medroxyprogesterone acetate in postmenopausal women showed no effects or even an increase in cardiovascular morbidity and mortality such as thrombosis or stroke. Therefore, conjugated equine estrogens alone or in combination with medroxyprogesterone acetate should not be recommended for the prevention or treatment of cardiovascular disease. Optimizing the risk factor profile such as cessation of smoking, normalizing body weight and blood pressure, regular physical activity, and statin treatment of patients with coronary artery disease remain important treatment options.