Cholesteryl ester transfer protein (CETP) mediates neutral lipid transport in plasma, resulting in a net transfer of cholesteryl ester from high density lipoprotein to very low density lipoprotein. CETP gene expression is regulated by cholesterol, and plasma CETP level increases in patients with hyperlipidemia and with cholesterol feeding. Simvastatin, unlike cholestyramine, reduces hydroxymethylglutaryl coenzyme A reductase activity and may decrease a cellular pool of cholesterol, which is regulatory for CETP gene expression. The effects of simvastatin and cholestyramine on plasma lipids and CETP in 24 male and 19 female patients with primary hypercholesterolemia were compared. Following a four-week placebo period, patients were randomly assigned to receive either simvastatin or cholestyramine. Medication was increased in a stepwise fashion (from 10 to 40 mg for simvastatin and from 8 to 24 g for cholestyramine) as required at six-week intervals to maintain a low density lipoprotein cholesterol (LDL-C) level below 3.4 mmol/L. At the end of the 18-week study, the mean dose of simvastatin was 28.6 mg/day and of cholestyramine 19.3 g/day. Simvastatin was more effective than cholestyramine in lowering LDL-C (-36.8% versus -27. 2%; P=0.031) and triglycerides (-8.5% versus +12.5%; P=0.045). Plasma CETP level decreased by 14.8% following treatment with simvastatin (P=0.003) but did not change following cholestyramine treatment. This study demonstrates that, compared with cholestyramine, simvastatin results in more favourable improvements in the plasma lipoprotein profile and also lowers plasma levels of CETP.