Apolipoprotein (apo) E2 and high insulin levels are associated with the severity of hypertriglyceridemia in patients with combined hyperlipidemia. To study how these determinants affect very low-density lipoprotein (VLDL) in combined hyperlipidemic patients, we characterized VLDL particles in 106 unrelated patients with combined hyperlipidemia. The study was performed after 9 weeks of standardized dietary intake and after an overnight fast. Patients heterozygous for apoE2 had significantly higher mean levels of VLDL cholesterol by 0.71 mmol/l (95% CI, 0.30 to 1.12 mmol/l, P < 0.005) and VLDL triglycerides by 0.88 mmol/l, (95% CI, 0.30 to 1.47 mmol/l, P < 0.005) compared to patients without apoE2. The VLDL triglyceride content per particle and the calculated diameter of the VLDL particles were similar in both groups, which indicate a higher number of circulating VLDL particles in heterozygous apoE2 carriers. Patients with high fasting insulin levels (> or = 80 pmol/l) had a higher mean serum VLDL triglyceride level by 0.56 mmol/l (95% CI, 0.04 to 1.07 mmol/l, P < 0.05). The calculated VLDL diameter was larger by 3.7 nm (95% CI, 1.2 to 6.2 nm, P < 0.005) and the particles contained more triglycerides by 2.7 weight percent (95% CI, 0.3 to 5.1 weight percent, P < 0.05). These insulin-dependent changes in VLDL particles were only present in the absence of apoE2. In conclusion, patients heterozygous for apoE2 have higher numbers of circulating VLDL particles, whereas patients with high fasting insulin levels have larger, triglyceride enriched VLDL particles.