Background: Interferon α(IFN-α) activated cellular sign- aling is negatively regulated by inhibitory factors, including the suppressor of cytokine signaling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-αtherapy and to determine hepatic expression of factors inhibiting IFN-αsignaling in obese and non-obese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-αor peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Results: Non-response (NR) to treatment occurred in 55%of patients with HCV genotypes 1 or 4 and 22%with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index ≥30 kg/m2 (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signaling may be one mechanism by which obesity reduces the biological response to IFN-α. Background: Interferon α (IFN-α) activated cellular signaling-aling is negatively regulated by inhibitory factors, including the suppressor of cytokine signaling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-α therapeutics and to determine hepatic expression of factors inhibiting IFN-α signaling in obese and non-obese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment with IFN-αor peginterferon alpha, either alone or in combination with ribavirin. time-polymerase chain reaction was performed to analyze hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 pat Results: Non-response (NR) to 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype Cirrhosis on pretreatment biopsy (p = 0.025), and body mass index ≥30 kg / m2 (p = 0.010) Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxykinase Following multivariate analysis, SOCS-3 mRNA expression was independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signaling may be one mechanism by which obesity reduces the biological response to IFN -α.