The effects of the two HMG CoA reductase inhibitors lovastatin and pravastatin in combination with 12-16 g cholestyramine on serum lipids were studied in 18 patients with severe primary hypercholesterolemia. Combined therapy of cholestyramine with lovastatin (80 mg daily) decreased low-density-lipoprotein (LDL) cholesterol by 44% (baseline 7.65 +/- 0.51 mM) and increased high-density-lipoprotein (HDL) cholesterol by 20% (baseline 1.22 +/- 0.12 mM) in 9 patients after 2 years. In 9 other patients with comparable baseline lipid values, cholestyramine plus pravastatin (40 mg daily) reduced LDL cholesterol to a comparable extent after 2 years (-43%, baseline 7.71 +/- 0.44 mM) and increased HDL cholesterol by 18% (baseline 1.06 +/- 0.11 mM). The combination with lovastatin led to a significant reduction in triglycerides level by 25% (baseline 1.63 +/- 0.24 mM), whereas the combination with pravastatin did not change triglycerides level (baseline 1.39 +/- 0.15 mM). Both drug regimens were well tolerated without serious side effects. The effects of both HMG CoA reductase inhibitors after 2 years were comparable to those after short-term intake and after 1-year therapy without loss of efficacy.