Significant advances have been made in the treatment of chronic hepatitis C virus (HCV) infection during the past 5 years. As a consequence, there is continuing enthusiasm for retreating patients who did not achieve sustained virological response (SVR) with previous therapy. Retreatment of non-responders to standard interferon monotherapy using interferon and ribavirin has yielded SVR rates of 12% to 15%. Retreatment with peginterferon and ribavirin has been more effective; achieving SVR rates of 34% to 40%. Retreatment of patients who relapsed after interferon monotherapy using standard interferon and ribavirin yielded SVR rates of 47%, whereas retreatment with peginterferon and ribavirin resulted in an SVR rate of about 60%. The major factors associated with a higher likelihood of an SVR after retreatment include previous relapse, previous treatment with interferon monotherapy, HCV genotypes 2 or 3, lower serum levels of HCV RNA, and having a significant decrease in HCV RNA levels during the initial course of therapy. These results help to focus retreatment with peginterferon and ribavirin on subsets of patients who are most likely to benefit.