IFN-α has been the cornerstone of chronic hepatitis C virus (HCV) treatment for over a decade. Yet, rates of sustained virologic response of HCV infection to interferon-based therapy, particularly in difficult-to-treat populations, have been disappointingly low. This is particularly true in HIV/HCV coinfection, in which less than a third of patients typically respond to therapy. New HCV protease inhibitors, most of which will need to be administered with pegylated interferon, are in development, but comprehensive, long-term data for their use in coinfected patients is not yet available. Understanding the basis of this population's poor response to interferon-based therapy is crucial to future exploration of new therapeutic options, immunotherapy and prognosis in HIV/HCV-coinfected population.