This study compares lovastatin and cholestyramine resin therapy in patients with severe primary hypercholesterolemia. Two hundred sixty-four patients on lipid-lowering diets were randomized equally to receive 12 g of cholestyramine resin, 20 mg of lovastatin, or 40 mg of lovastatin, each twice a day. The mean reductions among the three groups after 12 weeks' treatment in levels of total plasma cholesterol (-17%, -27%, and -34%, respectively) and low-density lipoprotein cholesterol ( - 23%, - 32%, and - 42%, respectively) and the median reductions in apolipoprotein B levels (-21%, -28%, and -33%, respectively) were all significantly different between groups. Similar mean increases in high-density lipoprotein cholesterol levels (8%, 9%, and 8%, respectively) and median increases in apolipoprotein A-I levels (7%, 6%, and 11%, respectively) were observed in all treatment groups. Cholestyramine resin treatment had no significant effect on very low-density lipoprotein cholesterol and apolipoprotein A-ll levels and produced a median 11% increase in plasma triglyceride concentration; in contrast, administration of either 20 or 40 mg of lovastatin twice a day was associated with median reductions in very low-density lipoprotein cholesterol levels (-34% and -31%, respectively) and plasma triglyceride levels ( - 21% and - 27%, respectively) and median increases in levels of apolipoprotein A-ll (8% and 13%, respectively). Adverse events in all treatment groups were preponderantly in the gastrointestinal tract; gastrointestinal tract symptoms that could be attributed to therapy with a specific drug occurred in 58% of the cholestyramine resin group, 13% of the 20-mg lovastatin group, and 14% of the 40-mg lovastatin group. The only drug-attributable serious adverse event was a reversible myopathy in a patient taking 40 mg of lovastatin twice a day. We conclude that lovastatin is both more effective and better tolerated than cholestyramine resin in the treatment of primary hypercholesterolemia.