HRT is likely to benefit menopausal women with concurrent conditions. In particular, women with atherosclerosis and its sequelae who use HRT may live longer. Our knowledge concerning the differential pharmacologic, biologic, and clinical effects of various estrogen preparations and routes is rudimentary, particularly in the sick climacteric woman. What data do exist, however, suggest that estrogen use is likely to improve the morbidity or mortality of women with coronary heart disease, myocardial infarction, congestive heart failure, hypertension, peripheral vascular disease, diabetes mellitus, stroke, and thromboembolic disorders. Whether there are any advantages to oral versus nonoral administration in these clinical circumstances has not been concretely determined. In order to minimize hepatic impact, it may be prudent to administer by a nonoral route estrogens that naturally occur in women to those with dyslipidemias, coagulopathies, liver disease, and cholelithiasis. Women who smoke are unlikely to accrue the full benefits of HRT. Although prospective, randomized clinical trials are expensive and tedious to execute, they are needed to determine the impact in sick menopausal women of estrogens and progestins in general and the different preparations, routes, and regimens in particular.