The North American-AIDS Cohort Collaboration on Research and Design (NA-ACCORD) began in 2006 as the representative of Region 1 of the leDEA initiative. The 22 single and multi-site clinical and classical epidemiologic HIV cohorts of the NA-ACCORD encompass most HIV/AIDS cohorts within North America. Over 100 sites in the US and Canada contribute data collected from over 100,000 HIV-infected and 150,000 HIV-uninfected participants. During the last 4 years, we established a strong collaborative infrastructure that capitalizes on the talents and expertise of a multi-disciplinary group of investigators that span basic science, clinical research, epidemiology, data informatics and biostatistics. We have been highly productive in addressing our original Aims and expanding our scientific focus to several areas of contemporary importance in HIV in North America. Our collaboration is well-positioned to successfully answer the key questions in practice today. We have three broadly-defined aims for the next funding cycle: Aim 1: Determine the clinical epidemiology of HIV infection in North America, with a focus on aging and the incidence and determinants of non-AIDS co-morbidities. Aim 2: Provide unique data on current and evolving trends, outcomes and comparative effectiveness of treatment of HIV infection in North America, with a focus on the timing of presentation for HIV care and the initial use of ART, determinants of long-term viral suppression, immune recovery, and clinical disease progression, the impact of hepatitis C co-infection, and the development of resistance. Aim 3: Capitalize on our large sample size to quantify and identify factors associated with important rare events and support translational research. The NA-ACCORD is a world-class collaboration of established HIV cohorts well-positioned to provide definitive answers to these issues of contemporary relevance in the U.S. and Canada. In addition, we will expand our collaboration with other leDEA regions to both inform future experience in resource-limited regions as the treatment of the epidemics mature, and to identify and understand differences in treatment, outcomes and prognostic factors that might inform future research and clinical care globally. RELEVANCE: The NA-ACCORD is the most comprehensive collaboration of HIV cohorts that exists within North America. Its large sample size, the comprehensiveness and quality of its data, combined with the expert use of state- of-the-art statistical methods will allow us to provide answers to critical questions of contemporary importance for the care of HIV-infected individuals in the U.S. and Canada.