Coinfection with hepatitis B virus (HBV) is not uncommon in human immunodeficiency virus (HIV)-infected individuals and patients with HIV-HBV coinfection are at high risk for progression of liver disease. Current guidelines regarding the treatment of HIV infection recommend that patients who are coinfected with HIV and HBV receive highly active antiretroviral therapy (HAART) with activity against hepatitis B. While HIV-HBV coinfected patients often experience liver enzyme elevations after starting antiretroviral therapy, acute liver failure (ALF) is rare and typically occurs with older antiretroviral agents with known potential for hepatotoxicity. We describe two cases of fatal ALF in the setting of HIV-HBV coinfection after initiation of HAART. These cases occurred despite treatment with antiretrovirals that have activity against HBV and highlight the challenges in distinguishing drug hepatotoxicity and HBV immune reconstitution inflammatory syndrome. HIV-HBV coinfected patients should be monitored closely when initiating HAART, even when treatment includes agents that have activity against HBV.