Objective: To evaluate the influence of 2 continuous combined estrogen-progestin replacement products, compared with unopposed estrogen and placebo, on cardiovascular risk markers in postmenopausal women in a randomized, double-blind, placebo-controlled trial. Methods: Two hundred seventy healthy postmenopausal women were randomly assigned to 1 of 4 treatment groups: placebo, unopposed 17-beta estradiol(1 mg), 1 mg of 17-beta estradiol with 0.25 mg of norethindrone acetate, or 1 mg of 17-beta estradiol with 0.5 mg of norethindrone acetate. The primary outcome variable was change from baseline in low-density lipoprotein cholesterol concentration. Additional outcome variables included changes in other serum lipid levels, hemostatic variables, and indicators of carbohydrate metabolism. Results: The low-density lipoprotein cholesterol level was reduced to a similar degree in all groups receiving active treatment (10%-14% from baseline; P=.001 for 17-beta estradiol with 0.5 mg of norethindrone acetate, P=.004 for 17-beta estradiol with 0.25 mg of norethindrone acetate, and P=.001 for 1 mg of 17-beta estradiol vs placebo). Compared with unopposed 17-beta estradiol, 17-beta estradiol with 0.5 mg of norethindrone acetate enhanced the reductions in total cholesterol and apolipoprotein B levels (P<.01 vs 17-<beta> estradiol). 17-beta Estradiol plus norethindrone blunted or reversed the increases in levels of high-density lipoprotein cholesterol, apolipoprotein A-I, and triglycerides produced by 17-beta estradiol alone. Effects of 17-beta estradiol plus norethindrone on hemostatic variables were similar to those of 17-beta estradiol except for factor VII activity, which was significantly reduced with 17-beta estradiol combined with 0.25 mg (P<.01) and 0.5 mg (P<.05) of norethindrone acetate. 17-beta Estradiol plus norethindrone appeared to blunt reductions in C-peptide and insulin levels produced by unopposed 17-beta estradiol but did not elevate these values compared with placebo. Conclusions: 17-beta Estradiol plus norethindrone produced favorable changes in most cardiovascular risk markers evaluated and has a profile distinct from that of unopposed 17-beta estradiol. The impact of these differences on cardiovascular events warrants investigation.