BackgroundInjection drug users (IDUs) and their sex partners account for an increasing proportion of new AIDS and HIV cases in the United States, but public debate and policy regarding the effectiveness of various HIV prevention programs for them must cite data from other countries, from non-street-recruited IDUs already in treatment, or other programs, and from infection rates for pathogens other than HIV.MethodsParticipants were recruited from the street at six sites (Baltimore [Maryland], New York [two sites], Chicago [Illinois], San Jose [California], Los Angeles [California], and at a state women's correctional facility [Connecticut]), interviewed with a standard questionnaire, and located and reinterviewed at one or more follow-up visits (mean, 7.8 months later). HIV serostatus and participation in various programs and behaviors that could reduce HIV infection risk were determined at each visit.ResultsIn all, 3773 participants were recruited from the street, and 2306 (61%) were located and interviewed subsequently. Of 3562 initial serum specimens, 520 (14.6%) were HIV-seropositive; at subsequent assessment, 19 people, all from the East Coast and Chicago, had acquired HIV. Not using previously used needles was substantially protective against HIV acquisition (relative risk [RR], 0.29; 95% confidence interval [CI], 0.11–0.80 ) and, in a multivariate model, was significantly associated with use of needle and syringe exchange programs (adjusted odds ratio [ORadj], 2.08; 95% CI, 1.15–3.85). Similarly, reduction of injection frequency was very protective against seroconversion (RR, 0.33; 95% CI, 0.14–0.80), and this behavior was strongly associated with participation in drug treatment programs (ORadj, 3.54; 95% CI, 2.50–5.00). In a separate analysis, only 37.5% of study-participants had sufficient new needles to meet their monthly demand.ConclusionsIn this large multicity study of IDUs in the United States, several HIV prevention strategies appeared to be individually and partially effective; these results indicate the continued need for, and substantial gaps in, effective approaches to preventing HIV infection in drug users.