Background Type III hyperlipoproteinemia is characterized by the accumulation of chylomicron and very low density lipoprotein (VLDL) remnants. Individuals with this disorder have a high risk of premature atherosclerosis, and hypolipidemic drugs are useful in their management. Methods We compared, in a double-blind, placebo-controlled, randomized crossed study, the effects of gemfibrozil (1200 mg/day) and simvastatin (20 mg/day) on lipids, apolipoprotein AI, apolipoprotein B, and apolipoprotein E and on lipids and apolipoprotein B content in VLDL, intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in 10 patients with type III hyperlipoproteinemia. Results Levels of total cholesterol, VLDL cholesterol, IDL cholesterol, and apolipoprotein B decreased with both drugs. Larger reductions in triglycerides (109 ± 28.2 mg/dL, P = .005), VLDL cholesterol (24.7 ± 10.9 mg/dL, P = .05), and VLDL triglycerides (86.3 ± 20.2 mg/dL, P = .003) were obtained with gemfibrozil compared with simvastatin. LDL cholesterol reduction was more effective with simvastatin than with gemfibrozil (44.3 ± 17.1 mg/dL, P = .03). HDL cholesterol after gemfibrozil was 5.71 ± 2.37 mg/dL higher than after simvastatin. Conclusions In patients with type III hyperlipoproteinemia gemfibrozil is more effective in reducing total triglyceride and VLDL lipid levels than simvastatin, and simvastatin is better in reducing LDL cholesterol than gemfibrozil is. IDL and apolipoprotein E levels were reduced similarly with both drugs. (Am Heart J 1999;138:156-62.)