Growing evidence suggests an association between lipid abnormalities and fatty acid binding protein (FABP) and microsomal triglyceride transfer protein (MTP) gene variants. Our objectives were to determine whether Ala54Thr FABP2 and G-493T MTP polymorphisms are associated with increased risks of insulin resistance syndrome (IRS) in youth and/or modify the expression of accompanying dyslipidemia. Our study of 1,742 French-Canadians aged 9, 13, and 16 years did not provide evidence of a potential predisposition to IRS related to either FABP2 or MTP genotypes. However, we observed a heterogeneity of the FABP2 effect by IRS status on total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), and apolipoprotein B (apoB) concentrations (P for interaction=0.045, 0.018, and 0.017, respectively). Among the metabolic components of IRS, only triglyceride (TG) displayed an interaction with FABP2 polymorphism: compared with Thr/Ala and Ala/Ala, the Thr/Thr genotype was associated with a steeper increase in TC, LDL-C, and apoB parallel to TG concentrations (P <0.001). IRS did not modify the associations between the MTP polymorphism and any of the biochemical parameters. Our study suggests that the effects of FABP2 allelic variations on lipid traits are context dependent, indicating that this variant may play an important role in cardiovascular pathogenesis in the presence of IRS or hypertriglyceridemia.