Although statins are effective lipid-lowering agents, the phenotypic and demographic predictors of such lowering have been less well examined. We enrolled 944 African-American and white men and women who completed an open-label, 6-week pharmacogenetics trial of 40 mg of simvastatin. The phenotypic and demographic variables were examined as predictors of the change in lipids and lipoproteins using linear regression analysis. On average, treatment with simvastatin lowered low-density lipoprotein (LDL) cholesterol by 54 mg/dl and increased high-density lipoprotein (HDL) cholesterol by 2 mg/dl. Compared with African-Americans, whites had a 3-mg/dl greater LDL reduction and a 1-mg/dl higher HDL elevation, independent of other variables, including baseline lipoprotein levels (p <0.01). Multivariate analyses revealed moderate subgroup differences, with older participants having a larger decrease in LDL cholesterol and apolipoprotein B levels compared with younger participants (p <0.001), women having larger increases in HDL than men (p <0.01), nonsmokers having larger decreases in LDL and triglyceride levels compared with smokers (p <0.05), those with hypertension having smaller decreases in apolipoprotein B than those without hypertension (p <0.05), and those with a larger waist circumference having a diminished lowering of triglycerides in response to treatment with simvastatin (p <0.01). In conclusion, treatment with simvastatin produced favorable lipid and lipoprotein changes among all participants. The magnitude of the lipid and lipoprotein responses, however, differed among participants according to a number of phenotypic and demographic characteristics.