The Saitama Postmenopausal Lipid Intervention Study was a multicenter, uncontrolled, collaborative study that investigated tolerability and sex-related differences in the response of serum lipids to simvastatin administered for 12 months in 122 postmenopausal women and 55 men with serum total cholesterol (TC) levels > or =220 mg/dL. With simvastatin treatment, TC and low-density lipoprotein cholesterol (LDL-C) levels decreased significantly at 1 month in both groups, and these decreased levels were maintained throughout treatment (P < 0.001). A significant decrease in triglyceride (TG) levels was also observed in both groups (P < 0.05). The mean percentage decreases in TC and LDL-C levels in women (20% and 28%, respectively) were significantly greater than those in men (15% and 20%, respectively) (P < 0.001). Mean percentage changes in TC and LDL-C levels in subgroups defined by stratification for baseline TC and LDL-C levels were also greater in women. There were no sex-related differences in the percentage changes in TG or high-density cholesterol levels, although the changes were influenced by baseline levels. Although the median dose of simvastatin (milligrams per kilogram of body weight) in women was significantly higher than in men (P < 0.001), the percentage changes in serum lipids were not correlated with the doses of simvastatin calibrated by body weight. Adverse reactions occurred in 8 men and 7 women, so there appeared to be no significant sex-related difference. Eleven patients had abnormal laboratory values. Simvastatin therapy for 12 months is well tolerated and effective for both women and men with hypercholesterolemia. Sex-related differences occurred in the response to simvastatin therapy of serum lipids, especially TC and LDL-C, with greater changes in lipid levels occurring in women.