A range of efficacies have been reported for biomedical HIV prevention interventions, including antiretroviral treatment, male circumcision, pre-exposure prophylaxis, microbicides and preventive vaccines. This range of efficacies likely results from the influence of multiple inputs and processes during trials, including the strength and target of the intervention, host factors, target population characteristics, level of HIV exposure and intervention dose. Expertise in social and behavioral science, in conjunction with basic science, clinical research, epidemiology, biostatistics and community, is needed to understand the influence of these inputs and processes on intervention efficacy, improve trial design and implementation, and enable interpretation of trial results. In particular, social and behavioral science provides the means for investigating and identifying populations suitable for recruitment into and retention in trials, and for developing and improving measures of HIV exposure and intervention dose, all within the larger socio-cultural context. Integration of social and behavioral science early in idea generation and study design is imperative for the successful conduct of biomedical trials and for ensuring optimal data collection approaches necessary for the interpretation of findings, particularly in cases of unexpected results.