Promising new tools for HIV prevention and treatment have stimulated global initiatives to “End the HIV Epidemic” and reach the “End of AIDS;” however, significant challenges to ending the global HIV epidemic remain. Biomedical advances for prevention and treatment will not reach their full potential without rigorous behavioral and social science research to optimize uptake, adherence, and equitable and effective implementation and scale-up. Thus, we propose a renewed HIV Center for Clinical and Behavioral Studies that expands on our history of conducting interdisciplinary HIV research and leverages new partnerships to maximize the potential of biomedical advances, addressing their availability and acceptability to the most vulnerable populations. The HIV Center is unique among NIMH AIDS Research Centers (ARCs) in being based in New York City (NYC), a continuing US AIDS epicenter in a state that has the greatest number of people living with HIV (PLWH) in the US, including ethnic/racial minority populations coping with extreme economic, health, and social disparities. In 2014, HIV Center investigators and other academicians, providers, advocates, and policy-makers joined the Office of the Governor of New York State (NYS) to develop a NYS Blueprint for Ending the Epidemic (EtE). The Blueprint provides the HIV Center with the unique opportunity to use our home city and state as a “laboratory” to study implementation of EtE initiatives and apply lessons learned to US and global epidemics. Thus, in the next five years, the HIV Center will be guided by the theme, The Science of Ending the HIV/AIDS Epidemic (EtE): Efficacy to Effectiveness at Scale, and its emphasis on implementation research and research at the intersection of behavioral, social, and biomedical sciences. The HIV Center brings together a cadre of investigators at the forefront of multiple disciplines to address three Specific Aims: (1) to catalyze intervention and implementation science research necessary to achieve EtE goals; (2) to translate research into culturally and structurally competent practice and policy for maximum public health impact; and (3) to increase the capacity of current and future generations of scientists, service providers, and community and policy leaders to create and implement biomedical, behavioral, social, and structural HIV prevention and treatment interventions to meet EtE goals. Our Cores ensure methodological and theoretical rigor, identify and rapidly respond to new trends in the epidemic, support critical research- practice partnerships, and train new scientists. We complement the Administrative and Development Cores with three Research Cores: (1) Statistics, Assessment, and Data Management (StAD) Core, focused on innovative analytic, assessment, and data management strategies; (2) Bio-Behavioral Core, focused on research at the interface of the biomedical and the behavioral and social sciences; and (3) Implementation Science and Health Outcomes (ISHO)...