Apolipoprotein (apo) E and apoC-III concentrations in VLDL and LDL are associated with coronary heart disease. We studied the relationship between apoE and apoC-III and the abnormal concentrations and distribution of apoB lipoproteins in 10 hypercholesterolemic and 13 hypertriglyceridemic patients compared with 12 normolipidemic subjects (mean age, 45 years). Sixteen distinct types of apoB lipoprotein particles were separated by first using anti-apoE and anti-apoC-III immunoaffinity chromatography in sequence and then ultracentrifugation [light VLDL, dense VLDL, IDL, and LDL, with apoE with or without apoC-III (E(+)C-III(+), E(+)C-III(-)) or without apoE with or without apoC-III (E(-)C-III(+), E(-)C-III(-))]. The concentrations of VLDL particles with apoC-III (E(+)C-III(+), E(-)C-III(+)) were increased in the hypertriglyceridemic group compared with the hypercholesterolemic and normolipidemic groups. These particles were the most triglyceride rich of the particle types, and their triglyceride content was twice as high in hypertriglyceridemics compared with the other two groups. Hypertriglyceridemics had a similar concentration of total E(-)C-III(-) particles compared with normolipidemics, but the E(-)C-III(-) particles were distributed more to VLDL and IDL than to LDL. Hypercholesterolemics, in contrast, were distinguished from the normolipidemic group by 2-fold higher concentrations of apoB lipoproteins without apoE or apoC-III (E(-)C-III(-)), mainly LDL, which had high cholesterol content. Nonetheless, both normolipidemics and hypercholesterolemics had apoC-III-containing VLDL, which comprised 68% and 43% of their total VLDL particles. E(+)C-III(-) particles were a minor type, comprising <10% of particles in all lipoproteins and patient groups. Therefore, VLDL particles with apoC-III may play a central role in identifying the high risk of coronary heart disease in hypertriglyceridemia, but their substantial prevalence in normolipidemics may be of clinical significance as well.