Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case-control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-β (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69-11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08-10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49-10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25-1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25-1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01-13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14-82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00-18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.