Since 1973 the portacaval shunt has been used as a treatment for homozygous familial hypercholesterolemia. Favorable results have been reported, but the mechanism or reduction of cholesterol is not clear. The objective of this research was to evaluate mechanisms of lipid alterations after portacaval shunting in Yucatan miniature swine. The animals were fed a high-fat diet, similar in composition to the average American diet, with or without added cholesterol. Controls were fed the atherogenic diet (+ cholesterol) for 8 months. Pigs were fed atherogenic or American diets for 8 months, then surgery (shunt or sham) was performed. They were continued on the diets for another 8 months. The vascular system was examined for the distribution and severity of atherosclerotic disease. Blood lipids and numerous biochemical indices were measured. Progression of atherosclerosis was slowed by portacaval shunting. Low density lipoprotein (LDL) concentrations were positively and high density lipoprotein (HDL) concentrations were negatively correlated with severity of atherosclerosis. Serum insulin concentrations were positively correlated with atherosclerosis. Cholesterol synthesis was increased by the shunting and decreased by cholesterol feeding. The cholesterol-fed swine is not an adequate model for familial hypercholesterolemia, but the results are consistent with inhibition of the atherosclerotic process and the involvement of lipoproteins and insulin in the mechanisms.