Previous studies have shown that simvastatin, a hydroxymethyl glutaryl coenzyme A reductase inhibitor, reduces plasma cholesterol levels when administered once a day. In the present study, the efficacy and tolerability of a morning and an evening dose were compared. The dosages employed were 2.5 and 5 mg for 12 weeks. This investigation was a double-blind, placebo-controlled study involving 172 hyperlipidemic subjects whose plasma cholesterol levels were higher than 220 mg/dl. During the study period, mean changes in plasma cholesterol level (from baseline) were -11% with the 2.5-mg q.a.m. regimen, -15% with the 2.5-mg q.p.m. regimen, -14% with the 5-mg q.a.m. regimen, and -21% with the 5-mg q.p.m. regimen. Each of these changes was statistically significant when compared with that in the placebo group (p less than 0.001). In addition, the reduction in cholesterol level was significantly greater with the evening regimen than with the morning regimen for both the 2.5-mg (p less than 0.05) and the 5-mg (p less than 0.05) dosages. The changes in triglyceride and high density lipoprotein cholesterol levels in each group were not significantly different from those in the placebo group. There were no differences in the incidence of clinical adverse reactions among the various treatment groups. In conclusion, when simvastatin was administered orally once per day in the evening, it reduced cholesterol levels to a significantly greater degree than when it was given in the morning.