The management of persons non-responsive to peginterferon and RBV therapy requires careful assessment of the liver disease stage and prior treatment course with respect to virologic response and tolerability. Re-treatment with interferon and RBV should be considered in persons with inadequate prior treatment andcorrectable factors as well as those with partial response to prior therapy (>2 log10 at week 12). However, during re-treatment, the milestone measure of treatment effectiveness is the achievement of an undetectable HCV RNA at re-treatment week 12; patients who do not have an undetectable HCV RNA level at this milestone should discontinue therapy. For patients who become undetectable, longer therapy (72 weeks) may increase the likelihood of SVR by reducing the rate of relapse. For patients who remain detectable, long-term interferon therapy is not uniformly recommended but may be considered in persons with baseline portal hypertension based on the findings of the EPIC3study. Persons with treatment failure should be referred to clinical trials of novel therapeutic agents.