Transaminase elevations occur more frequently after beginning antiretroviral therapy in HIV-positive patients co-infected with hepatitis C virus (HCV). The mechanism of liver injury in these individuals is unknown, although immune reconstitution phenomena have been postulated. In 42 HIV/HCV co-infected individuals followed after beginning potent antiretroviral therapy, the development of liver injury was not associated with significant changes in serum HCV-RNA levels nor with greater CD4 cell increases. Underlying chronic hepatitis may thus increase the risk of liver toxicity by other mechanisms.