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In the context of the current concern about HIV prevention efforts, this article addresses the issues of efficacy and effectiveness. We argue that the success of treatments and associated increasing dominance of biomedicine has meant that far too little attention has been paid to effectiveness, that is, to the impact an HIV prevention program or intervention achieves in the real world, under resource constraints, in entire populations. Although biomedicine has, appropriately, investigated the efficacy of a number of new prevention technologies and modeled the impact of "test and treat," issues relating to the provision, acceptability, adoption, and sustained use of prevention technologies, both old and new, have not been fully addressed. As HIV is a profoundly social disease with its causes and consequences deeply embedded in social, cultural and political processes, social scientists need to be heard and work with biomedical scientists to ensure the success of HIV prevention.