Background:Hepatitis C virus (HCV) infection as a worldwide health problem is associated with cirrhosis and hepatocellular carcinoma. With current treatment regimen, pegylated interferon (PEG-IFN) plus ribavirin, sustain virological response (SVR) is achieved in only 50% of infected individuals. In HCV infection, an inappropriate ratio of cytokines may affect the benefit of antiviral therapy. Given the polymorphisms in regulatory regions of cytokines genes may influence cytokines production.Objectives:We aimed to investigate both the frequency of genotypes and alleles of interferon gamma (IFN-γ) gene at +874A/T, +2109A/G, and -183G/T loci in HCV-infected patients and their associations with response to therapy.Patients and Methods:A total of 158 patients were included and treated with PEG-IFN plus ribavirin. The presence of HCV infection in patients was confirmed by reverse transcription polymerase chain reaction, and genomic DNA was extracted from peripheral leukocytes using salting out method. IFN-γ gene polymorphisms were identified by polymerase chain reaction using sequence specific primers and restriction fragment length polymorphism analysis on genomic DNA.Results:Of 158 patients, 110 (69.5%) subjects achieved SVR and 48 (30.5%) subjects did not respond to therapy. The frequency of AA genotype (P = 0.001; OR: 11.2; CI: 2.26-63.21) and A allele (P = 0.01; OR: 3.23; CI: 1.23 8.56) of IFN-γ gene at +2109 locus were significantly different between the responder and non-responder subjects infected with genotype 1. Regardless of HCV genotype, the frequency of AG genotype was also higher in responder group than those who did not respond to therapy (P = 0.041; OR: 05.05; CI: 1.05-33.25)). In case of IFN-γ gene at +874 locus, there was no difference in genotypes and alleles frequencies between the responder and non-responder subjects infected with HCV genotypes 1 and 3. Haplotype analysis showed no association between haplotypes and response to therapy. All participants had G/T genotype at -183 locus.Conclusions:Our findings indicate that heterogeneity at +2109 locus of IFN-γ gene but not at +874 locus could interfere with successful therapy in patients infected with HCV genotype 1.