The design of studies evaluating the safety and efficacy of interventions for HIV prevention is challenging in the US context, where there is low generalized prevalence. HIV incidence is sufficiently high in the at-risk US population of men who have sex with men that prevention trials using HIV infection end points are feasible. In other US populations at higher risk of HIV exposure, efficacy trials of HIV prevention are likely not feasible. However, for interventions where efficacy is already established, conducting trials that test different implementation strategies in these populations could provide definitive evidence about how to achieve high levels of coverage.