We have previously demonstrated an apolipoprotein E (apo E) mutant, apo E5, associated with hyperlipidemia and atherosclerotic vascular diseases. To investigate the possible mechanism of apo E5 involvement in the development of hyperlipidemia, we have isolated the apo E isoprotein and determined its binding activity to LDL (low density lipoprotein) receptors. It was shown that the apo E5 isoprotein was two times more active for binding to LDL receptors than apo E3. The concentration of apo E, at which 50% of 125I-labeled LDL bound to the receptor was displaced, was 29 ng/ml for apo E5 and 63 ng/ml for apo E3. This result suggests that the high affinity of apo E5 to LDL receptors results in a high uptake of apo E5-containing lipoproteins by the liver and leads to a down-regulation of LDL receptors in the liver. We can postulate that individuals with apo E5 are susceptible to hypercholesterolemia and in consequence to atherosclerosis.