OBJECTIVE To consider whether the addition of a progestin or an androgen to estrogen replacement therapy (ERT) will modify the effects of the estrogen upon arterial disease risk. METHODS Review of selected literature. METHODS Population studies, clinical trials, and laboratory investigations. METHODS Postmenopausal women. METHODS Exogenous progestin or androgen in hormone replacement regimens. METHODS Lipids and lipoproteins, carbohydrate metabolism, prostaglandin and thromboxane metabolism, fibrinolysis and coagulation, fat distribution, and arterial tone. RESULTS The favorable lipid and lipoprotein changes induced by estrogens are modified by progestin and androgen addition. Some of these modifications are potentially adverse (progestin lowering of high-density lipoprotein-2 cholesterol) but some are potentially beneficial (progestin lowering of triglycerides). Recent studies suggest that progestins may not reverse the estrogen-induced reduction in low-density lipoprotein cholesterol. The scant data upon the effects of androgens on lipid and lipoproteins suggest that the addition of T to the estrogen may block the rise in high-density lipoprotein cholesterol seen in women receiving estrogen alone. Because of a lack of appropriate data, it is this author's opinion that the clinical effects of progestin or T addition to ERT cannot be predicted at this time. Further studies are urgently needed to clarify how progestin or T addition modify estrogen effects upon carbohydrate, prostaglandin and thromboxane metabolism, upon fibrinolysis and coagulation, and upon arterial tone.