Soy protein favorably alters serum lipids and lipoproteins in hypercholesterolemic individuals, thereby reducing cardiovascular disease risk. The primary purpose was to determine the effect of soy protein (40 g/d) on circulating lipids and lipoproteins or coagulation and fibrinolytic factors in normocholesterolemic and mildly hypercholesterolemic perimenopausal women. We also determined the contribution of coagulation and fibrinolytic and other factors (e.g., body size and composition; serum estrogens, ferritin, iron; dietary intake) to lipid profiles. Subjects were randomly assigned to treatment: isoflavone-rich soy (n = 24), isoflavone-poor soy (n = 24), or whey control (n = 21) protein. We measured circulating lipids and lipoproteins at baseline, wk 12 and wk 24, and coagulation/fibrinolytic factors at baseline and wk 24. Coagulation and fibrinolytic factors were not adversely affected by treatment. Treatment did not alter lipid profiles in mildly hypercholesterolemic (n = 30) or in all subjects combined. Time significantly (P < 0.001) affected serum total cholesterol, triacylglycerol, LDL cholesterol and HDL cholesterol concentrations. We could not attribute changes over time to various factors, but at baseline accounted for 57% of the variability in HDL cholesterol (P < or = 0.0001) and for 50% in the total to HDL cholesterol ratio (P < or = 0.0001). Dietary vitamin E and % energy from fat had positive effects, whereas plasma plasminogen activator inhibitor-1, fibrinogen, body weight and serum ferritin had negative effects on HDL and total to HDL cholesterol. Isoflavone-rich or isoflavone-poor soy protein had no effect on lipid profiles or coagulation and fibrinolytic factors, whereas the effect of time suggested that the hormonal milieu during the menopausal transition may have overridden any detectable treatment effect on lipids. The relationship between coagulation factors and serum lipids should be examined further as indices of cardiovascular disease risk in midlife women.