Drug-induced liver injury (DILI) is the elevation of liver enzyme and/or bilirubin levels caused by the use of a medication or drug. In patients with human immunodeficiency virus (HIV) infection, some of these events may not be directly caused by medication. Acute viral hepatitis, reactivation of hepatitis B virus or hepatitis C virus (HCV) infection, and/or alcohol use may play roles. Elevated transaminase levels are a signal of liver injury, but most cases improve despite continuation of drug therapy. Approximately 33% of patients with HIV infection are coinfected with HCV. Patients with HIV or HCV infection are more prone to DILI, possibly because of impaired hepatocyte defense mechanisms. HCV coinfection is associated with a 2-10-fold chance of developing elevated transaminase levels during highly active antiretroviral therapy (HAART). Patients with HIV/HCV coinfection should not be denied HAART. Instead, they should be followed-up with monthly liver function tests and referred to specialists if grade 3 or 4 liver enzyme elevations occur.