The success rate in HCV treatment of HIV/HCV-coinfected patients is still unsatisfactory and new strategies are required to improve the effectiveness of current regimens and eventually optimize the oncoming new antiviral drugs. This article assesses the findings of a recently published paper comparing pharmacokinetics, pharmacodynamics and HCV decay with twice-weekly dosing of pegylated IFN-α-2a versus the standard weekly dosing, and weight-based ribavirin. A more rapid HCV-RNA decline was observed in the twice-weekly pegylated interferon arm and associated with a higher induction of interferon-stimulated genes, despite a similar pharmacokynetic profile between the two dosing schedules. This promising novel therapeutic approach to improve sustained virologic response in difficult-to-treat populations is discussed in relation to the key findings of the article.