OBJECTIVE: To provide an overview of the National Institute of Mental Health (NIMH) Collaborative HIV/STD Prevention Trial taking place in five populations at risk of HIV and sexually transmitted diseases in China, India, Peru, Russia, and Zimbabwe, including the rationale, study management, methods, and proposed data analyses. DESIGN: The Trial will scientifically evaluate the effectiveness of the community popular opinion leader (C-POL) community-level HIV prevention intervention that was adapted for use in the various cultures within the resource limitations faced by service providers in world regions threatened by high rates of HIV infection. METHODS: The study phases consist of an ethnographic study, pilot studies, an epidemiological study, and a community-randomized trial. The Trial uses the C-POL intervention, which researchers selected on the basis of research that shows the intervention's success in populations vulnerable to HIV risk behavior in the United States, and has the potential to be applied in a variety of international settings. RESULTS: Trial results will be tabulated by and across country by randomization assignment. Results will include a careful review of data to substantiate original assumptions used in the study design. Data collection will not conclude until August 2007. CONCLUSION: Although data collection is incomplete, researchers have learned lessons throughout the development of the study. These include the importance of preliminary epidemiological studies; the close monitoring of biological testing, follow-up rates and process measures at international sites; the tailoring of assessments and interventions to various cultures; regular communication; and a review of the timeline to accommodate Institutional Review Board clearances. © 2007 Lippincott Williams & Wilkins, Inc.