OBJECTIVE: To determine the efficacy and safety of pravastatin in the treatment of subjects with Type III hyperlipoproteinemia. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: Four lipid research clinics in the United States. PATIENTS: Twenty subjects between 18 and 70 years old with three diagnostic features of Type III hyperlipoproteinemia: very-low-density lipoprotein cholesterol (VLDL-C)/total plasma triglyceride ratio in excess of 0.30; beta-migrating VLDL pattern on agarose-gel electrophoresis; and the homozygous apolipoprotein E phenotype E(2)/E(2). After 4 weeks of dietary control, the subjects were eligible if their mean plasma total cholesterol level was at least 250 mg/dl and mean plasma trigylceraide level was at least 220 mg/dL. INTERVENTIONS: Subjects were randomly assigned to pravastatin 40 mg hs or placebo hs at the start of the first 6-week double-blind treatment period. After completing this phase, subjects entered a 4-week placebo/drug washout phase before crossing over to the opposite treatment for the second 6-week double-blind treatment period. MEASUREMENTS: Plasma VLDL-C and low density lipoprotein cholesterol (LDL-C) after ultracentrifugation and total triglyceride, cholesterol and high-density lipoprotein cholesterol (HDL-C) after 6 weeks of treatment; adverse clinical events and abnormal laboratory results. RESULTS: After 6 weeks of pravastatin theraphy, plasma levels of VLDL-C and LDL-C decreased 49% and 39%, respectively (p less-than-or-equal 0.01 vs. placebo). Total cholesterol and triglyceride concentrations decreased 36% and 22%, respectively (p less-than-or-equal 0.001 vs. placebo). Levels of HDL-C increased 8% (p less-than-or-equal 0.01 vs. placebo). Pravastatin was tolerated well. One marked laboratory abnormality, an asymptomatic elevation of creatine phosphokinase, resolved upon completing pravastatin treatment. CONCLUSIONS: Pravastatin lowers plasma VLDL-C, LDL-C, total cholesterol, and triglyceride and raises HDL-C in subjects with Type III hyperlipoproteinemia. The safety profile is excellent. Pravastatin reductase inhibitor therapy affords a useful approach to the management of Type III or remnant removal disease.