The non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine (NVP), efavirenz (EFV), and delaviridine (DLV) are increasingly being used to treat HIV infection. Studies have shown excellent tolerance and efficacy and less development of virological resistance with HIV regimens that include NNRTIs. Nevertheless, abnormalities in liver enzymes are common in patients with HIV infection, and there are multiple etiologies for these abnormalities, including drug toxicity, viral hepatitis, opportunistic infections, and substance abuse. In particular, highly active antiretroviral therapy (HAART) can result in hepatotoxicity through a variety of mechanisms, such as mitochondrial toxicity, lipodystrophy syndrome, and steatohepatitis. The NNRTIs have been most frequently implicated in hypersensitivity reactions. NVP-containing HAART regimens may be more hepatotoxic than are those with EFV and DLV, at least for the first 6 weeks, although the data are still contradictory. Coinfection with hepatitis C and B viruses appears to significantly increase the risk of toxicity, and therefore all patients should be screened for viral hepatitis prior to commencing HAART. Close monitoring of transaminases is suggested in all patients commencing HAART, especially those with preexisting liver disease and coinfection with viral hepatitis.