Liver enzyme elevations are common in human immunodeficiency virus (HIV)-infected patients, and their diagnosis or management may be difficult because of the intricacies of the pathogenic mechanisms involved. These include hepatotoxicity related to the highly active antiretroviral therapy (HAART) regimen, idiosyncratic or immunoallergic mechanisms, and direct cytotoxicity enhanced by an underlying liver disease. Liver enzyme abnormalities may also reflect hepatitis B (HBV) or hepatitis C (HCV) infection, which each have their own risks for chronic immune-mediated liver disease (including hepatitis flare after immune reconstitution) and of direct cytotoxicity. Finally, other factors may affect liver deterioration, including alcohol-related liver disease, nonalcoholic steatohepatitis associated with metabolic syndromes (e.g., hyperlipidemia, diabetes, or being overweight) that are potentially HAART related, and use of medication or illicit drugs (e.g., methamphetamine). A better understanding of these complex interactions, including adjustments of dosages of antiretroviral drugs, will probably help in the management of HIV-infected patients with liver enzyme abnormalities.