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The combination of pegylated interferon (IFN) with ribavirin is the standard of care for chronic hepatitis C. Response rates range from 50 to 90% for genotype 1 and 2/3 which also differ in the duration of treatment (48 vs 24 weeks, respectively). Therapy if given with weight-based dosing may be shortened from 24 to 12, 14 or 16 weeks (genotypes 2 and 3), and from 48 to 24 weeks (genotype 1) in case of hepatitis C virus (HCV) clearance at week 4, without reducing sustained virologic response (SVR). Conversely, prolonging treatment for 72 weeks in those with only a decrease of viral load at week 4, i.e. “slow responders” increases SVR rates by preventing relapse. In spite of such progress, over half of patients are relapsers or nonresponders. If the previous treatment was suboptimal, retreatment with higher doses or longer duration may be beneficial unless an individual was a ‘null responder’ previously. New promising anti-HCV molecules (antiproteases and antipolymerases), some with potent antiviral activity, are in phase II trials but appear to require the addition of IFN and ribavirin to maintain viral suppression. Other immunomodulatory agents such as new IFN or therapeutic vaccines and alternatives to ribavirin are also under development. Future regimens should improve efficacy and provide shorter and better-tolerated combination therapy.