Introduction: The aim of this study was to evaluate the interaction between dietary fatty acids and the genetic variant of APOC3 rs5128 3238C>G in relation to metabolic syndrome (MetS) components in adults. Materials and Methods: In this matched nested case-control study, 755 MetS subjects and 755 controls were selected from among participants of the Tehran Lipid and Glucose Study. Dietary intake was determined using a valid and reliable food frequency questionnaire. APOC3 was genotyped by the conventional polymerase chain reaction and restriction fragment length polymorphism. Results: Mean ages of men and women were not different in cases and controls. The frequency of C allele was 81%, which did not differ in cases and controls or in men and women. Compared to CC genotype, low HDL-C risk was increased in women with the CG+GG genotypes and with cholesterol intakes ≥208 mg/day (OR: 1.93). In men with the CG+GG genotypes and saturated fatty acid (SFA) intakes ≥9.8% of energy, OR of high diastolic blood pressure (BP) was 2.15(1-1.46), compared to individuals with SFA intake <9.8% of energy and CC genotype. Compared to the CC genotype, the risk of high diastolic BP was higher in men carrying the G allele and consuming mono-unsaturated fatty acid (MUFA) intakes ≥9.4% of energy. Conclusions: Results demonstrate a nutri-genetic interaction between rs5128 and fat intakes in relation to components of MetS individuals with G allele carriers and higher intakes of cholesterol, MUFA or SFA had higher risk of low HDL-C and hypertension than the CC genotype.