The effects of conjugated equine estrogen and subsequent cyclical progestogen supplementation on lipoprotein and apolipoprotein AI levels were investigated in three groups of postmenopausal women. Unopposed conjugated equine estrogen (0.625 mg) lowered total cholesterol 4-8% and low-density lipoprotein (LDL) cholesterol 12-19% below pre-treatment levels in all three groups. Levels of highdensity lipoprotein (HDL) cholesterol and apolipoprotein AI were increased 9-13 and 9-18%, respectively, with unopposed estrogen. The increase in HDL cholesterol was mainly due to increases in the high-density lipoprotein 2 (HDL 2) subfraction. Addition of medroxyprogesterone acetate, norethindrone acetate, or d, l-norgestrel at doses shown previously to provide protection against endometrial hyperplasia reversed some of the beneficial estrogen effects, reducing levels of HDL cholesterol 14-17%, HDL 2 cholesterol 22-37%, and apolipoprotein AI 11-15% from those obtained cholesterol 22-37%, and apolipoprotein AI 11-15% from those obtained with unopposed estrogen. The LDL cholesterol levels fell 12-19% with unopposed estrogen but remained 7-12% below baseline when progestogens were added. These observations demonstrate that after 3 months of treatment, all three progestogens reversed some of the favorable effects of unopposed estrogen on lipoproteins but permitted a continued modest reduction in LDL cholesterol.