In the field of HIV prevention, there is renewed interest in operations research (OR) within an implementation science framework. The ultimate goal of such studies is to generate new knowledge that can inform local programmes and policies, thus improving access, quality, efficiency and effectiveness. Using four case studies from the USAID-funded Research to Prevention (R2P) project, we highlight the strategic use of OR and the impact it can have on shaping the focus and content of HIV prevention programming across geographic and epidemic settings and populations. These case studies, which include experiences from several sub-Saharan African countries and the Caribbean, emphasize four unique ways that R2P projects utilized OR to stimulate change in a given context, including: (1) translating findings from clinical trials to real-world settings; (2) adapting promising structural interventions to a new context; (3) tailoring effective interventions to underserved populations; and (4) prioritizing key populations within a national response to HIV. Carefully crafted OR can bridge the common gap that exists between research-generated knowledge and field-based practice, lead to substantial, real-world changes in national policies and programmes, and strengthen local organizations and the use of data to be more responsive to a given topic or population, ultimately supporting a locally tailored HIV response.