Background: Metabolic syndrome (MetS) is related with all-cause mortality. Caveolin-1 (Cav-1) has been widely studied in dyslipidemia, and several studies have indicated that Cav-1 genetic variations may correlate with dietary intake of fatty acids. The aim of the current study was therefore to evaluate the interaction of Cav-1 rs3807992 with types of dietary fatty acid in MetS risk factor status Methods: This cross-sectional study was carried out on 404 overweight and obese females. Dietary intake was obtained from a 147-item FFQ. The CAV-1 genotype was measured using the PCR-RFLP method. Anthropometric values and serum levels (TC, LDL, HDL, TG, FBS) were measured by standard methods. Results: It was observed that the (AA+AG) group had significantly higher BMI, WC and DBP (P=0.02, P=0.02 and P=0.01, respectively) and lower serum LDL, HDL and TC (P < 0.05) than the GG group. It was found that A allele carriers were at higher odds of MetS (P= 0.01), abdominal obesity (P=0.06), increased TG concentration (P=0.01), elevated blood pressure (BP) (P=0.01), increased glucose concentration (P=0.45), and decreased HDL-cholesterol concentration (P=0.03). Moreover, the interaction of Cav-1 and SFA intake was significant in terms of MetS (P=0.01), LDL (P=0.03), DBP (P=0.01) and LDL/HDL (P=0.05). Additionally, the (AA+AG) group was significantly related to PUFA intake in terms of MetS (P=0.04), TG (P=0.02), glucose (P=0.02) and HOMA-IR (P= 0.01). Conclusions: Higher PUFA consumption might attenuate the Cav-1 rs3807992 associations with MetS, and individuals with greater genetic predisposition appeared to have a higher risk of MetS, associated with higher SFA consumption To date, studies on this polymorphism have been animal studies and have not been performed on healthy and obese human society For the first time , this study provides information on the interaction of different fatty acids with the Caveolin gene, which is functionally effective in lipid metabolism