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 nig/d, n=10; (2) fish 011 (himega 6 g/d, equivalent to 3 g to-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%pJ<.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. High-density lipoprotein cholesterol (HDL-C) and apo A-1 did not change on any single or combined drug therapy. The effect of drug therapy on lipoprotein fractions was also determined. Lipoproteins of intermediate-density lipoprotein (IDL; Svedberg flotation units [Sf] 12 to 60) and very-low-density lipoprotein (VLDL; Sf>60) were isolated by ultracentrifugation. With pravastatin treatment, the concentration of VLDL and IDL did not change significantly, even though there was a trend toward a lower concentration of IDL lipids. With fish oil, the concentration of VLDL lipids fell significantly by at least 37%p><.05), whereas IDL remained unchanged. However, combined therapy of pravastatin plus fish oil reduced the concentration of both VLDL and IDL by at least 35% (bothp<.01). In addition, combined therapy reduced the TC-to-TG ratio in VLDL by 25% (p<.05). These results showed that in patients with mixed hyperlipidemia pravastatin lowered TC more than TG, whereas fish oil lowered TG but not TC. The combination of pravastatin plus fish oil reduced both TC and TG and appeared safe to use in the short term. Fish oil decreased the concentration of VLDL. However, the combination of pravastatin and fish oil effectively reduced the concentration of VLDL and IDL.