Thrice-weekly interferon alfa-2b plus ribavirin has been the standard of care for chronic hepatitis C; however, a majority of patients fail to achieve a sustained virological response with this treatment. Peginterferon alfa-2a (40 KD), interferon alfa-2a conjugated to a 40 kDa branched polyethylene glycol moiety, exhibits sustained absorption and reduced renal clearance, resulting in antiviral pressure throughout a once-weekly dosing schedule. Peginterferon alfa-2a (40 KD) has superior virological efficacy to interferon alfa-2a, and elicits histological improvements in patients with and without sustained virological response. Peginterferon alfa-2a (40 KD) is effective in patients infected with viral genotype 1 and those with liver cirrhosis. Viral RNA measurements at 12 weeks can be used to predict the probability of achieving sustained virological response to peginterferon alfa-2a (40 KD) therapy. Peginterferon alfa-2a (40 KD) has comparable safety to interferon alfa-2a. The addition of ribavirin to peginterferon alfa-2a (40 KD) further enhances the therapeutic benefit for patients with hepatitis C.