Although familial hypercholesterolemia (FH) has been well characterized in terms of the etiology of the major lipoprotein abnormality, that of low density lipoproteins (LDL), less information is available on changes in other lipoproteins which could influence the atherogenic process in this disorder. The present study has focused on such potential abnormalities by studying in detail the lipoprotein association of apolipoprotein E (apo E) in a large group of subjects homozygous for FH. Total plasma apo E levels in homozygous subjects were significantly elevated (p less than 0.001) relative to heterozygous subjects which were, in turn, significantly greater (p less than 0.001) than controls (137.6 micrograms/ml, 69.4 micrograms/ml, 46.5 micrograms/ml respectively). After separation of plasma lipoproteins by 4% agarose chromatography, an increased mass of apo E in lipoproteins of intermediate size was present; this may reflect the absence of LDL receptors that normally mediate their clearance. Homozygous FH subjects also demonstrated an increased mass of apo E-enriched high density lipoproteins (HDL) of large size, but a reduction in HDL cholesterol and apo A-I. The increase in the potentially atherogenic remnant lipoproteins and the decrease in HDL are associated with an increased risk for atherosclerosis, even in the absence of the LDL elevation, which is characteristic of FH. The increase in apo E-enriched HDL could reflect a compensatory mechanism that permits reverse cholesterol transport in the absence of LDL receptors.