The impact of apo E polymorphism on interindividual variation in plasma lipid, lipoprotein concentrations, and LDL subfraction profiles was studied in 201 well-defined patients (88 men and 103 women) with familial combined hyperlipidemia (FCH). When corrected for the concomitant influences of age, gender and obesity, the allelic variation in the apo E gene was shown to explain a statistically significant portion of the variability in lipid and (apo)lipoprotein concentrations. Carriers of the apo epsilon 2 allele exhibited a substantially higher plasma triglyceride concentration and a lower low density lipoprotein (LDL) cholesterol level, while subjects with the apo epsilon 4 allele had significant higher total plasma cholesterol and LDL cholesterol levels. In line with this observation, our FCH population was characterized by an over-representation of the apo E4 allele as compared with a Dutch standard population (chi 2 = 55.2, P < 0.0001). The contribution of apo E polymorphism to trait variability was different between sexes for plasma triglyceride, VLDL cholesterol, VLDL triglycerides, and high density lipoprotein (HDL) cholesterol levels. Apo E polymorphism had no impact on chemical composition of VLDL; for LDL particles the apo epsilon 2 allele was associated with a lower cholesterol to protein (C/P) ratio, whereas the opposite was true for the apo epsilon 4 allele. Despite the demonstrated impact of apo E polymorphism on plasma lipids and LDL chemical composition, in all phenotypic groups a dense LDL subfraction profile predominated. Thus, apo E polymorphism contributes to the lipid phenotypic expression in FCH, whereas further evidence was obtained that a dense LDL subfraction profile is an integral feature of FCH.