Triglyceride-rich lipoprotein (TRL) remnants have been strongly implicated in the pathogenesis of atherosclerosis. To further investigate plasma remnant lipoprotein metabolism, we have determined the plasma concentration of apolipoprotein (apo) E (by polyclonal enzyme-linked immunoassay) in remnant-like lipoproteins, isolated by automated gel filtration chromatography as a fraction intermediate in size between VLDL and HDL. In normolipidemic subjects (n=12), 1.2±0.1 mg/dL (33±2%, mean±SE) of total plasma apoE was associated with this fraction (termed ISL apoE). In hypercholesterolemic (type IIa, n=12), hypertriglyceridemic (type IV, n=12), and mixed hyperlipidemic (type IIb, n=12) subjects, mean ISL apoE concentrations were 2.1±0.2, 2.5±0.2, and 3.8±0.4 mg/dL, respectively (P<.001 versus normal values) (45±2%, 32±2%, and 44±2% of total). ISL apoE was 8.7±1.4 mg/dL (42±3%) in type III dyslipidemic subjects (apoE2/2, n=8). ISL apoE was positively correlated with plasma triglyceride (r=.41, P<.01), and at any given level of plasma triglyceride, subjects with an apoE2/2 or apoE3/2 phenotype tended to have a higher concentration of ISL apoE (P<.01) than apoE3/3 or E4/3 individuals. ISL apoE was also correlated (P<.001) with total plasma cholesterol (r=.66), TRL cholesterol (r=.49), TRL apoE (r=.47), LDL apoB (r=.42), and LDL+HDL triglyceride (r=.74). These results suggest that (1) a significant proportion of plasma apoE resides within an intermediate-sized remnant-like lipoprotein fraction in both normolipidemic and hyperlipidemic subjects; (2) plasma remnant lipoprotein accumulation is associated with an elevation in ISL apoE concentration; and (3) ISL apoE concentration is significantly correlated with various proatherogenic lipid parameters and may itself be a potentially important atherogenic index.