This study compared the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, fish oil, and placebo on plasma lipids and lipoproteins in patients with mixed hyperlipidemia. After an initial run-in phase, 32 patients were randomized for 6 weeks to either (1) pravastatin 40 mg/d, n = 10; (2) fish oil (himega 6 g/d, equivalent to 3 g omega-3 fatty acids/d), n = 10; or (3) placebo. After single drug therapy, in the pravastatin group mean total plasma cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (apo) B fell significantly by 23% (P < .001), 30% (p < .001), and 26% (P < .01), respectively. LDL Stokes' diameter did not change. In the fish oil group mean plasma triglycerides (TG) fell 30% (P < .05), LDL Stokes' diameter increased from 25.0 to 25.9 nm (P < .05), and there was a nonsignificant increase in LDL-C. There were no changes in the placebo group. To assess the effect of the combination of pravastatin plus fish oil therapy, all patients, except one woman from the placebo group who developed nausea on fish oil, then took combined therapy of pravastatin 40 mg/d plus fish oil 6 g/d for an additional 12 weeks. In each case, there were no clinically significant episodes of muscle tenderness or elevation of creatine phosphokinase or alanine aminotransferase. After 12 weeks of combined therapy of pravastatin plus fish oil, there were significant reductions in the mean TC, TG, LDL-C, and apoB in the three groups compared with baseline levels.(ABSTRACT TRUNCATED AT 250 WORDS)