Abstract: The aim of this study was to examine interferon-gamma (IFN-γ), anti-C1q antibodies, myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) and anticardiolipin antibodies in the serum of biopsy-proven chronic hepatitis C patients before and after interferon (IFN)-alpha and ribavirin therapy to address whether or not viral clearance is related to these biomarkers and to explore a possible association between the pattern of these immune response parameters with the virological and biochemical status of Hepatitis C Virus (HCV). The serum levels of IFN-γ, anti-C1q, myeloperoxidase ANCA and anticardiolipin antibodies were assayed on 64 patients with chronic hepatitis C virus infection before and 48 weeks after treatment with pegylated IFN-α plus ribavirin and compared with sera from 20 normal control subjects. Serum levels of ICN-γ, anti-C1q, myeloperoxidase ANCA and anticardiolipin antibodies were significantly higher in HCV patients in comparison to healthy controls (p<0.0001). IFN-γ levels were significantly increased after 48 weeks of antiviral treatment when compared to pretreatment serum levels and it was significantly more elevated in responder HCV patients than non responders. While as, both anti-C1q antibodies and myeloperoxidase ANCA levels were significantly decreased after 48 weeks antiviral treatment in the HCV patients. Moreover, IFN-γ levels (but not other studied biomarkers) in HCV patients correlated significantly with high alanine aminotransferase (ALT) levels as well as with high viral load (r = 0.675, p≤0.05, r = 0.912, p≤0.001, respectively). In conclusion, IFN-gamma might be useful in predicting the clinical outcome of the combination therapy of pegylated-IFN alpha and ribavirin, as well as responsiveness to IFN-alpha-based therapy may be improved by using easily assessed immune response biomarkers such as interferon gamma, anti-C1q antibodies. Furthermore, early treatment in HCV patients with multiple serological abnormalities will prevent further autoimmune response which eventually could prevent marked extrahepatic complications.