The effects of colestipol HCl resin and clofibrate on plasma lipid and lipoprotein levels were compared in 65 patients with primary hypercholesterolemia. Patients were randomly assigned to treatment with colestipol (in progressive doses of 15, 20, and 30 g/day), clofibrate (2 g/day), or placebo resin; lipoprotein levels were determined at months 0, 2, 4, 6, and 9. The colestipol group received both colestipol and clofibrate during months 7 through 9 of the study. After 6 months of treatment, mean plasma total cholesterol fell from 333 to 266 (P less than 0.01) on colestipol, and from 329 to 270 (P less than 0.05) on clofibrate. More patients responded, however, to colestipol than to clofibrate. Both drugs also produced significant reductions in LDL cholesterol levels, and clofibrate lowered plasma triglycerides as well. HDL cholesterol level did not change significantly on either medication. The placebo group showed no change in any of the parameters studied. A significant difference was not observed between the effects of 15 g/day of colestipol and those of the higher doses studies. Addition of clofibrate to colestipol did not enhance the latter's hypocholesterolemic action.