Type III hyperlipoproteinemia is characterized by increased plasma levels of triglycerides and cholesterol, palmar-tuberoeruptive xanthoma, and premature cardiovascular disease. Three major classes of molecular defects will predispose patients to develop type III hyperlipoproteinemia: a deficiency in apolipoprotein E, a structural defect in the E apolipoprotein, and a functional defect in the liver receptor system. Most patients with type III hyperlipoproteinemia have a structural defect in apolipoprotein E associated with increased synthesis and decreased catabolism of apolipoprotein E, delayed catabolism of chylomicron remnants, and development of plasma lipoprotein abnormalities characteristic of type III hyperlipoproteinemia. Analysis of cardiovascular disease in patients with type III hyperlipoproteinemia showed extensive coronary and peripheral vascular atherosclerosis indistinguishable from the atherosclerosis of non-hyperlipidemic and other dyslipoproteinemic patients. The xanthoma and elevated plasma cholesterol and triglyceride levels in patients with type III hyperlipoproteinemia respond to dietary and drug therapy.