The results presented here reveal some barriers to HIV prevention efforts targeting MSM and FSW in Swaziland, but also potential opportunities for effective programming. The data highlight the need for a targeted HIV prevention strategy that integrates behavioral, biomedical, and structural components. Future research and programming efforts must work towards developing and implementing multilayered interventions for KP in Swaziland that recognize the complex relationship between levels of risk and the need for sensitive, population-specific programming.