To investigate the potential effects of high-dose 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor on plasma phytosterol, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), hypercholesterolemic subjects received 40 or 80 mg/d simvastatin in a 24-week prospective clinical trial. Plasma lipid levels were analyzed enzymatically, and plasma phytosterol concentrations were determined using gas-liquid chromatography. The change in the plasma phytosterol-campesterol level was used as an indicator of cholesterol absorption in humans. Simvastatin treatment reduced plasma campesterol (-24%, P = .017) but did not affect circulating stigmasterol and sitosterol levels. A dose of 80 mg/d simvastatin produced a larger decrease (P = .050) in plasma campesterol (0.1680 mmol/L) than 40 mg/d (0.0237 mmol/L) versus baseline. There was a positive correlation between plasma campesterol and TC both before (r = .54, P = .027) and after (r = .63, P = .009) treatment. Plasma TC and TG levels did not differ between groups receiving 40 or 80 mg/d simvastatin. Simvastatin treatment reduced circulating TC, LDL-C, and TG by 40%, 50%, and 33% (P<.007), respectively. There was no significant effect of simvastatin on plasma HDL-C, but the HDL-C/LDL-C ratio increased 1.3-fold (P<.0001). In conclusion, this HMG-CoA reductase inhibitor reduces the plasma campesterol level, a marker of cholesterol absorption, which may contribute to the mechanism by which simvastatin decreases circulating cholesterol levels.