OBJECTIVE As the acquired immunodeficiency syndrome (AIDS) epidemic among drug users enters its third decade in the United States, it is important to consider the role playing by substance abuse treatment in the prevention of human immunodeficiency virus (HIV) infection. METHODS The authors review the research literature, examining findings from studies with behavioral and serologic measures on the association among treatment participation, HIV risk reduction, and HIV infection. RESULTS Numerous studies have now documented that significantly lower rates of drug use and related risk behaviors are practiced by injecting drug users (IDUs) who are in treatment. Importantly, these behavioral differences, based primarily on self-report, are consistent with studies that have examined HIV seroprevalence and seroincidence among drug users. CONCLUSIONS The underlying mechanism of action suggested by the collective findings of the available literature is rather simple-- individuals who enter and remain in treatment reduce their drug use, when leads to fewer instances of drug-related risk behavior. This lower rate of exposure results in fewer infections with HIV. The protective effects of treatment, however, can only be achieved when programs are accessible and responsive to the changing needs of drug users. Future research needs to be directed at developing a better understanding of the factors that enhance treatment entry and retention.