The introduction of inhibitors of cholesterol biosynthesis offers a new approach to treatment of hypercholesterolemia. One such agent, lovastatin (formerly, mevinolin), causes significant reductions in plasma cholesterol levels. This action can be enhanced by bile acid sequestrants. In this study, lovastatin and colestipol hydrochloride together were administered to ten patients with primary moderate hypercholesterolemia. Compared with a control period, the combined-drug therapy caused a 36% reduction in plasma total cholesterol level, a 48% decrease in low-density lipoprotein (LDL) cholesterol level, and a 17% increase in high-density lipoprotein cholesterol level. The reduction in LDL cholesterol level was due to three factors: (1) a 27% decrease in the production rate of LDL, (2) a 20% increase in fractional catabolic rate of LDL, and (3) a 15% depletion of cholesterol in LDL particles. This major reduction in LDL cholesterol level produced by combined-drug therapy may be valuable for prevention of coronary heart disease in high-risk patients with primary moderate hypercholesterolemia.