Autoimmune hepatitis (AIH) is a progressive, chronic hepatitis that has rarely been reported in HIV-infected individuals. Among patients who are candidates for hepatitis C virus (HCV) treatment, screening for AIH should be considered, because interferon has the potential to cause fulminant hepatic failure in the setting of immune-mediated injury. During a 4-year period, we identified four HIV-infected patients who were referred for evaluation of persistently elevated aminotransferases, two of whom were also infected with HCV. Serologic testing and the hepatic histologic appearance were consistent with AIH. Although each patient initiated treatment with corticosteroids and immunosuppressive agents, all four eventually developed life-threatening infectious or adverse metabolic effects that resulted in treatment discontinuation. Of note, one HIV/HCV co-infected patient was able to initiate HCV treatment with interferon after AIH remission was documented. While these cases illustrate that AIH can produce hepatic injury in virally infected individuals, we recommend that treatment for AIH in HIV-infected patients should be individualized after careful consideration of the potential risks and likely benefits.