In summary, the study of type III hyperlipoproteinemia has provided important insights into lipoprotein metabolism that have helped to elucidate several functional roles for apo E and have provided a better understanding of the mechanisms whereby specific lipoproteins may be atherogenic or anti-atherogenic. The molecular defect in type III hyperlipoproteinemia and dysbetalipoproteinemia is the presence of a mutant form of apo E, usually apo E2, that is defective in binding to both apo B,E(LDL) and apo E receptors. The receptor-defective apo E results in an impaired clearance of remnant lipoproteins (beta-VLDL). In addition, the abnormal apo E may impair the lipolytic processing of hepatic beta-VLDL through its involvement in lipid transfer or exchange processes. The accumulation of beta-VLDL may provide the most direct mechanism responsible for the accelerated atherosclerosis observed in type III hyperlipoproteinemia, a mechanism that involves the receptor mediated uptake of beta-VLDL by macrophages, which are then converted to arterial foam cells. Alterations in the HDL of patients with type III hyperlipoproteinemia further support the concept that HDL are anti-atherogenic. The increase in HDL-with apo E provides insight into the role of these cholesterol-enriched HDL in reverse cholesterol transport and in the cellular redistribution of cholesterol, processes whereby cholesterol deposition may be reversed. It should be stressed that both the accumulation of beta-VLDL and alterations in HDL (reduction in typical HDL and an increase in HDL-with apo E) are associated with accelerated atherogenesis in animals fed high levels of fat and cholesterol. Although valuable information has been gained concerning the mechanisms involved in type III hyperlipoproteinemia by the study of the disease, the clinical expression of this disorder is variable, ranging from hypocholesterolemia to marked hypercholesterolemia in subjects with the same molecular defect (E2/2). This variability in expression is more easily understood when one considers the various factors that can promote the hyperlipoproteinemia and when one considers the mechanisms of action whereby these factors may exacerbate the effects of the presence of an abnormal apo E. In most cases, development of type III hyperlipoproteinemia requires that a second event (a predisposing environmental factor or a second genetic defect) be associated with the primary genetic defect (an abnormal form of apo E).