Researchers are increasingly recognizing the importance of addressing sexual and drug-related HIV risk within the context of intimate relationships rather than solely focusing on individual behaviors. Practical and effective methods are needed to recruit, screen, and enroll the high risk and hard-to-reach couples who would most benefit from HIV interventions, such as drug-using female sex workers (FSWs) and their intimate, non-commercial partners. This paper outlines a bi-national, multidisciplinary effort to develop and implement a study protocol for research on the social context and epidemiology of HIV, sexually transmitted infections (STI), and high risk behaviors among FSWs and their non-commercial male partners in Tijuana and Ciudad Juarez, Mexico. We provide an overview of our study and specifically focus on the sampling, recruitment, screening, and successful enrollment of high risk couples into a public health study in this context.