Background: HepatitisCvirus (HCV) infection is a global health problem. Most cases of HCVinfection do not resolve spontaneously.Combination therapy with pegylated interferon- (PegIFN-alpha) and ribavirin (RBV) is the standard treatment for patients withHCV infection. The success of treatment is affected by several host, viral, and treatment factors. Available works have demonstratedsignificant role of interleukin ۲۸B (IL۲۸B) polymorphisms in predicting HCV infection treatment outcomes. This suggests the possibilityof tailored therapy in HCV infected patients. HCV is one of the most common causes of liver disease worldwide. If untreated,this infection can develop chronic hepatitis in ۵۰%-۸۵% of patients. The aim of current study is to determine the association ofinterleukin-۲۸B (IL-۲۸B) rs-۱۲۹۷۹۸۶۰ polymorphism in response to peginterferon-alpha (PegIFN-alpha) and ribavirin combinationtherapy in Iranian patients with chronic hepatitis C genotype ۱ infection.Methods: This cross-sectional study was carried out on ۷۰ Iranian patients with chronic hepatitis C infection (genotype ۱) receivingPegIFN-alpha and ribavirin. DNAwas extracted from blood samples. Specific primers were used to amplify targeted polymorphisms.Results: In this study, ۷۱.۴% of patients reached sustained virological response (SVR). The prevalence of CC, CT and TT genotypeswere ۳۸.۶%, ۴۲.۸% and ۱۸.۶% respectively. The rate of SVR was ۹۶.۳ for CC genotype, whereas this rate was ۶۶.۷ for CT and ۳۰.۸ for TTgenotypes. We found an association between end of treatment response (ETR) and IL-۲۸B genotypes as ۱۰۰% of patients bearing CCgenotype reached ETR, but ETR rate was ۴۵.۸۵% in CT group and ۱۰.۲% in TT group. Six months follow-up showed that there was asignificant difference between response to treatment in patients IL-۲۸B-CC and TT (P < ۰.۰۰۱). Data regression analysis showed thatCC genotype was an independent predicting factor, significantly associated with higher SVR (P = ۰.۰۰۵ (OR=۳۶.۱; ۹۵% CI = ۳ - ۴۳۴.۲)).In contrast, absence of C allele (TT genotype) was significantly correlated with the failure of response (P = ۰.۰۰۵ (OR = ۳۶.۱; ۹۵% CI =۳ - ۴۳۴.۲)).