Triglyceride-rich lipoproteins contain both apolipoproteins E (ApoE) and C-III (ApoC-III), which show opposite functional properties. The relationships between the ApoE (epsilon2/epsilon3/epsilon4) gene polymorphism and ApoC-III/ApoE ratio has never been investigated. A large population (n=552) of cardiovascular patients, without diabetes and/or lipid-lowering therapy, with or without metabolic syndrome (MetSyn), was genotyped for epsilon2/epsilon3/epsilon4 polymorphism and their ApoCIII/ApoE ratio was evaluated. A second group of patients (n=76) with peripheral artery disease was also genotyped and their ApoC-III/ApoE ratios were measured in HDL and non-HDL fractions. Subjects with E2 had higher and E4 carriers lower TG,ApoE and ApoC-III levels, respectively. The ApoCIII/ ApoE ratio showed an opposite trend, gradually increasing from E2/E2 to E4/E4 subjects. MetSyn patients also had an elevated ApoC-III/ApoE ratio and E4 carriers were more frequent in MetSyn patients (OR 2.08 with a 95%CI 1.22-3.5). The distribution of ApoC-III/ApoE ratio was confirmed also in the second group, with lower values in E2/E3 and higher in E3/E4 subjects. Similar results were obtained for the concentrations measured in non-HDL fractions, but not in the HDL fractions. ApoE epsilon2/epsilon3/epsilon4 gene polymorphism is a determinant of the relative proportion of apolipoprotein C-III to E. Carriers of the unfavourable E4 allele present the highest ApoCIII/ApoE ratio and are twofold more frequent among individuals affected by MetSyn.