Injecting drug users (IDUs) are at high risk for infection by human immunodeficiency virus (HIV) and other blood-borne pathogens. In the United States, IDUs account for nearly one-third of the cases of acquired immunodeficiency syndrome (AIDS), either directly or indirectly (heterosexual and perinatal cases of AIDS where the source of infection was an IDU). IDU also account for a substantial proportion of cases of hepatitis B (HBV) and hepatitis C (HCV) virus infections. The primary mode of transmission of HIV among IDUs is parenteral, through direct needle sharing or multiperson use of syringes. Despite high levels of knowledge about risk, multiperson use of needles and syringes is due primarily to fear of arrest and incarceration for violation of drug paraphernalia laws and ordinances that prohibit manufacture, sale, distribution, or possession of equipment and materials intended to be used with narcotics. It is estimated that in 1997 there were approximately 110 needle exchange programs (NEPs) in North America. In part, because of the ban on the use of Federal funds for the operation of needle exchange, it has been difficult to evaluate the efficacy of these programs. This chapter presents data from the studies that have evaluated the role of NEPs in HIV prevention. Evidence for the efficacy of NEPs comes from three source: (1) studies originally focused on the effectiveness of NEPs in non-HIV blood-borne infections, (2) mathematical modeling of data on needle exchange on HIV seroincidence, and (3) studies that examine the positive and negative impact of NEPs on HIV and AIDS. Case-control studies have provided powerful data on the positive effect of NEPs on reduction of two blood-borne viral infections (HBV and HCV) For example, a case-control study in Tacoma, Washington, showed that a six-fold increase in HBV and a seven-fold increase in HCV infections in IDUs were associated with nonuse of the NEP. The first federally funded study of needle exchange was an evaluation of the New Haven NEP, which is legally operated by the New Haven Health Department. Rather than relying on self-report of reduced risky injection drug use, this study utilized mathematical and statistical modeling, using data from a syringe tracking and testing system. Incidence of HIV infection among needle exchange participants was estimated to have decreased by 33% as a result of the NEP. A series of Government-commissioned reports have reviewed the data on positive and negative outcomes of NEPs. The major reports are from the National Commission on AIDS; the U.S. General Accounting Office; the Centers for Disease Control/University of California; and the National Academy of Sciences. The latter two reports are used in this chapter. The aggregated results support the positive benefit of NEPs and do not support negative outcomes from NEPs. When legal restrictions on both purchase and possession of syringes are removed, IDUs will change their syringe-sharing behaviors in ways that can reduce HIV transmission. NEPs do not result in increased drug use among participants or the recruitment of first-time drug users.