Many HIV prevention funding agencies require the use of evidence-based behavioral interventions (EBIs) previously shown to be effective through rigorous outcome evaluation. Often, the implementing agency's setting or target population is different than those in the original implementation and evaluation. The Centers for Disease Control and Prevention Division of HIV/AIDS Prevention, in collaboration with internal and external partners, developed draft guidance to adapt an EBI to fit the cultural context, risk determinants, risk behaviors, and unique circumstances of the agency without competing with or contradicting the core elements and internal logic. The guidance described in this article provides a systematic approach to help agencies identify the most appropriate intervention for their target population and agency capacity, monitor the process, and evaluate the outcomes of the adapted intervention. This guidance, currently being piloted with five community-based organizations, will be revised and disseminated at the conclusion of project activities.