Co-infection with hepatitis C virus and human immunodeficiency virus results in increased fibrotic progression, decreased time to development of cirrhosis, and higher mortality associated with end-stage liver disease than infection with hepatitis C virus alone. Therefore, effective treatment intervention is critical. Standard combination therapy with interferon plus ribavirin historically has failed to provide consistent and significant sustained viral response rates. Recent efforts have focused on evaluation of peginterferons combined with ribavirin. Major randomized multicenter clinical trials have redefined the treatment of choice with yields of sustained viral response for hepatitis C up to 40% with peginterferon and ribavirin in co-infected patients. Human immunodeficiency virus control can be maintained during and after therapy for hepatitis C virus. Important adverse-event profiles associated with drug interactions between didanosine and ribavirin have been described.