Effects of cholestyramine treatment for 75 days on whole body cholesterol balance and hepatic HMG-CoA reductase and cholesterol-7-α-hydroxylase activities were studied in hypercholesterolemic swine. Sixteen male Yorkshire swine (10 kg) were divided into four groups; three groups were fed a high cholesterol (HC) diet for 50 days. One group was then switched to mash, the second was given cholestyramine, 12 gm daily, and the third was left on the high cholesterol diet, all for an additional 75 days. The fourth group was maintained on mash throughout the 125 days. Data for the cholesterol balance parameters, retention, excretion, and synthesis, were obtained during the terminal week. Hepatic HMG-CoA reductase and cholesterol-7-α-hydroxylase activities were assayed terminally. Cholestyramine reduced serum cholesterol concentrations in hypercholesterolemic swine very effectively although the reduction was not as complete as in those swine switched to mash diet. The drug also reduced whole body cholesterol retention. These changes appeared to be due to increases in both acidic and neutral steroids in the feces. Accompanying increases in whole body cholesterol synthesis probably partially offset the beneficial effect of increased steroid excretions. In vitro hepatic HMG-CoA reductase activities correlated well with whole body cholesterol synthesis determined by the balance method as well as with fecal steroid excretions. Cholesterol-7-α-hydroxylase activities of the liver microsomes correlated well with the amount of fecal bile acid excretion.