Paraoxonase-1 (PON1), a high-density lipoprotein (HDL) associated enzyme, is involved in the metabolism and detoxification of insecticides and pesticides. Three polymorphisms within the PON1 gene affect the enzyme activity. Two of these (L55M and Q192R) are located at the coding region and the third (-107C/T) is in promoter region. We performed a case-control study in order to elucidate the possible contribution of variability within PON1 at three mentioned positions to the risk of MS in a South-East Iranian population. DNA was isolated from peripheral blood of patients (N = 119) with MS and healthy controls (N = 201). Allelic polymorphisms at positions Q192R, L55M and -107C/T in the PON1 gene were studied by Amplification Refractory Mutation System (ARMS)-PCR. It was observed that genotypes RR and QR + RR of Q192R locus significantly increased the risk of MS (OR = 2; 95% CI: 1.17-3.40, P = 0.0001 and OR = 1.62; 95% CI: 1.0-2.63; P = 0.05, respectively). The risk in patients with MM and LM + MM genotypes at the L55M locus was marginal (OR = 1.33; 95% CI: 0.68-1.85; P = 0.34 and OR = 1.12; 95% CI: 0.68-1.85; P = 0.73 respectively). The CC genotype at -107C/T locus also increased the risk of metabolic syndrome, but was not significant. This association was somewhat stronger when combined genotypes at Q192R and L55M loci were analyzed (OR = 3.30; 95% CI: 1.34-8.24; P = 0.007). Our results, in this first study, provide evidence for association of PON1 gene polymorphisms with the risk for metabolic syndrome.