PURPOSE: Animal research and cross-sectional studies suggest that serum lipid concentrations may influence cognitive function, mood, and behavior, but few clinical trials have studied these effects. SUBJECTS AND METHODS: In this double-blind investigation, 209 generally healthy adults with a serum low-density-lipoprotein (LDL) cholesterol level of 160 mg/dL or higher were randomly assigned to 6-month treatment with lovastatin (20 mg) or placebo. Assessments of neuropsychological performance, depression, hostility, and quality of life were conducted at baseline and at the end of the treatment period. Summary effect sizes were estimated as z scores on a standard deviation (SD) scale. RESULTS: Placebo-treated subjects improved between baseline and posttreatment periods on neuropsychological tests in all five performance domains, consistent with the effects of practice on test performance (all P <0.04), whereas those treated with lovastatin improved only on tests of memory recall (P = 0.03). Comparisons of the changes in performance between placebo- and lovastatin-treated subjects revealed small, but statistically significant, differences for tests of attention (z score = 0.18; 95% confidence interval (CI), 0.06 to 0.31; P = 0.005) and psychomotor speed (z score = 0.17; 95% CI, 0.05 to 0.28; P = 0.004) that were consistent with greater improvement in the placebo group. Psychological well-being, as measured several ways, was not affected by lovastatin. CONCLUSION: Treatment of hypercholesterolemia with lovastatin did not cause psychological distress or substantially alter cognitive function. Treatment did result in small performance decrements on neuropsychological tests of attention and psychomotor speed, the clinical importance of which is uncertain.