BACKGROUND Drug hepatotoxicity is a potentially serious adverse reaction of antiretroviral therapy in human immunodeficiency virus-infected patients. The impact of this problem in the routine treatment of patients with human immunodeficiency virus infection is poorly defined. OBJECTIVE Our aim was to determine what clinical features are associated with hepatotoxicity in human immunodeficiency virus-infected patients receiving antiretroviral therapy. METHODS Consecutive patients in a primary care-based human immunodeficiency virus clinic were evaluated for hepatotoxicity. Clinic records were used to obtain patient characteristics, as well as independent variables including CD4+ count, coexisting hepatitis C and current alcohol use. RESULTS Sixty-five patients taking antiretroviral therapy were evaluated. Twenty-four were identified to have antiretroviral hepatotoxicity. An age over 40 years (P=0.019), an absolute CD4+ count of less than 310 cells/mL (P=0.002) and coexisting hepatitis C infection (P=0.035) were significantly associated with hepatotoxicity. Patients older than 40 years had a sevenfold increased risk (risk ratio, 6.9; 95% confidence interval, 1.7-27.3) and those with an absolute CD4+ count of less than 310 cells/mL had a tenfold increased risk (risk ratio, 10.2; 95% confidence interval, 2.5-41.9) for antiretroviral hepatotoxicity, in comparison with those who were younger or who had a greater absolute CD4+ count. Of the eight patients documented to have coexisting hepatitis C infection, six (75%) were in the antiretroviral hepatotoxicity group. CONCLUSIONS An age older than 40 years and an absolute CD4+ count of less than 310 cells/mL were significantly associated with antiretroviral-induced hepatotoxicity. The majority of our patients with chronic hepatitis C had hepatotoxicity from antiretroviral therapy.