The occurrence of human immunodeficiency virus (HIV) disease and hepatitis C is common in injection drug users, most of whom are opioid dependent. Methadone pharmacotherapy has been the most widely used treatment for opioid addiction in this population. Methadone has significant, adverse drug-drug interactions with many antiretroviral therapeutic agents that can contribute to nonadherence and poor clinical outcomes in this high-risk population. The present article summarizes current knowledge about interactions between methadone and antiretroviral medications. Buprenorphine is the newest agent available for the treatment of opioid dependence and may have fewer adverse interactions with antiretroviral agents. Buprenorphine has a significant pharmacokinetic interaction with efavirenz but no pharmacodynamic interaction; therefore, simultaneous administration of these drugs is not associated with opioid withdrawal, as has been observed with methadone. This promising finding may simplify the treatment of opioid-dependent patients with HIV disease and should also improve clinical outcomes for persons coinfected with HIV and hepatitis C virus.