The metabolism of apolipoprotein E (apoE) has received major emphasis in the past year. ApoE is elevated in animals with experimental hypercholesterolemia and atherosclerosis. In addition, patients with Type III hyperlipoproteinemia (HLP) have an abnormal apoE, elevated levels of apoE, and accelerated atherosclerosis. ApoE from normal subjects, Type V HLP patients (indistinguishable from normal apoE) and Type III HLP patients was purified, radioiodinated and injected into normal and Type III HLP patients. Type III HLP patients had 4 times the normal apoE level and the residence time for normal and Type V apoE was 2 times normal. Type III apoE had a prolonged residence time in both normal individuals and Type III HLP patients. These results indicate that Type III HLP patients have a catabolic defect for Type V apoE. In addition they indicate that Type III apoE is abnormal and is metabolized at a slower catabolic rate in both normal individuals and patients with Type III HLP. These studies represent the first demonstrated molecular defect in an apolipoprotein which results in hyperlipidemia.