In this paper we discuss the epidemiology and natural history of human immunodeficiency virus (HIV) infection in users of injection drugs. Use of injection drugs plays a central role in the HIV infection/AIDS epidemic in the United States, Europe, and many parts of the developing world. The significance of this role has been underappreciated until quite recently because of a number of factors. One factor has been systematic, albeit inadvertent, underreporting of cases of HIV disease and AIDS in drug injectors as a consequence of the initially narrow surveillance case definition for AIDS. A measure of this phenomenon has been the disproportionately larger increment of new cases in this population with each successive revision of the Centers for Disease Control and Prevention's surveillance case definition for AIDS. Other reasons for the underappreciation of the magnitude and consequences of HIV infection and AIDS in injection drug users include the lack of necessary diagnostic facilities in the institutions where drug users are often treated, high mortality rates among HIV-infected drug users for whom a diagnosis of AIDS has not yet been made, the severe marginalization of this population and its lack of advocates, and the localization of the initial epidemic in this population to certain geographic areas.