OBJECTIVE: To review the challenges of designing behavioral and biological outcome measures for the multinational NIMH Collaborative HIV/STD Prevention Trial and provide the rationale for selecting these measures. DESIGN: Although many different evidence-based prevention programmes have been developed, few have been evaluated in different countries, cultures, and populations. One issue in evaluating the generalized efficacy of any prevention approach is to identify a set of common outcome measures useful across diverse settings and peoples. The Trial is designed to evaluate whether the community popular opinion leader intervention can be adapted cross-nationally and cross-culturally for different populations and still retain its efficacy. METHODS: Literature reviews, investigator experience, ethnographic study, pilot studies, and epidemiological studies were used to select the endpoints for the Trial. RESULTS AND CONCLUSION: Both biological and behavioral data will be obtained at baseline and 12 and 24 months post-baseline. Communities that receive the intervention will be compared with matched control communities on two primary outcomes: (i) a change in self-reported unprotected sexual acts with non-spousal, non-live-in partners; and (ii) the incidence of sexually transmitted disease (STD), defined as a composite index of viral and bacterial STD. © 2007 Lippincott Williams & Wilkins, Inc.