Injection drug use contributes to considerable global morbidity and mortality associated with human immunodeficiency virus (HIV) infection and AIDS and other infections due to blood-borne pathogens through the direct sharing of needles, syringes, and other injection equipment. Of approximately 16 million injection drug users (IDUs) worldwide, an estimated 3 million are HIV infected. The prevalence of HIV infection among IDUs is high in many countries in Asia and eastern Europe and could exacerbate the HIV epidemic in sub-Saharan Africa. This review summarizes important components of a comprehensive program for prevention of HIV infection in IDUs, including unrestricted legal access to sterile syringes through needle exchange programs and enhanced pharmacy services, treatment for opioid dependence (ie, methadone and buprenorphine treatment), behavioral interventions, and identification and treatment of noninjection drug and alcohol use, which accounts for increased sexual transmission of HIV. Evidence supports the effectiveness of harm-reduction programs over punitive drug-control policies.