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While disease surveillance for HIV/AIDS is now widely conducted in the United States, effective HIV prevention programs rely primarily on changing behavior; therefore, behavioral data are needed to inform these programs. To achieve the goal of reducing HIV infections in the U.S., the Centers for Disease Control and Prevention, in cooperation with state and local health departments, implemented the National HIV Behavioral Surveillance System (NHBS) for injecting drug users (IDUs) in 25 selected metropolitan statistical areas (MSAs) throughout the United States in 2005. The surveillance system used respondent-driven sampling (RDS), a modified chain-referral method, to recruit IDUs for a survey measuring HIV-associated drug use and sexual risk behavior. RDS can produce population estimates for specific risk behaviors and demographic characteristics. Formative assessment activities—primarily the collection of qualitative data—provided information to better understand the IDU population and implement the surveillance activities in each city. This is the first behavioral surveillance system of its kind in the U.S. that will provide local and national data on risk for HIV and other blood-borne and sexually transmitted infections among IDUs for monitoring changes in the epidemic and prevention programs.