Research synthesis, through qualitative or quantitative systematic reviews, allows for integrating results of primary research to improve public health. We examined more than 2 decades of work in HIV prevention by the Centers for Disease Control and Prevention's (CDC's) HIV/AIDS Prevention Research Synthesis (PRS) Project. We describe the context and contributions of research synthesis, including systematic reviews and meta-analyses, through the experience of the PRS Project. We reviewed PRS Project publications and products and summarized PRS contributions from 1996 to July 2020 in 4 areas: synthesis of interventions and epidemiologic studies, synthesis methods, prevention programs, and prevention policy. PRS Project publications summarized risk behaviors and effects of prevention interventions (eg, changing one's perception of risk, teaching condom negotiation skills) across populations at risk for HIV infection and intervention approaches (eg, one-on-one or group meetings) as the HIV/AIDS epidemic and science evolved. We used the PRS Project cumulative database and intervention efficacy reviews to contribute to prevention programs and policies through identification of evidence-based interventions and development of program guidance. Subject matter experts and scientific evidence informed PRS Project products and contributions, which were implemented through strategic programmatic partnerships. The contributions of the PRS Project to HIV prevention and public health efforts in the United States can be credited to CDC's long-standing support of the project and its context within a federal prevention agency, where HIV programs and policies were developed and implemented. The effect of the PRS Project was likely facilitated by opportunities to directly influence program and policy because of connections with other research translation activities and program and policy decision making within CDC.