We propose to create the North American AIDS Cohort Collaboration on Research and Design (NAACCORD) in response to the International Databases to Evaluate AIDS RFA. The NA-ACCORD is designed to be widely representative of HIV care in the United States and Canada, and is comprised of both academic medical centers and community-based facilities that deliver HIV primary and specialty care. Further, it combines classical epidemiologic and clinical HIV cohorts in a unique and robust collaboration that includes both HIV-seropositive and seronegative persons. The NA-ACCORD consists of three major Cores - Administrative, Data Management, and Epidemiology/Biostatistics - that provide an infrastructure for efficient regional data collection and management, and the conduct of analyses to answer scientific questions of importance. Critical to our structure is the collaboration of investigators with a high level of scientific and methodologic expertise and HIV clinical experience to both identify questions of intraregional and interregional importance, and design and implement the analyses necessary to answer these questions. Our Core Aims are designed to answer questions that we have identified as most critical to the contemporary treatment of HIV-infection in North America. A large and growing number of HIV-infected persons in North America have received multiple antiretroviral (ARV) regimens with few apparent options for continuing treatment because of HIV resistance. The optimal management of these patients is unclear, and there are substantial methodologic challenges in addressing this issue. The rapid expansion of ARV options, with changes in tolerability, toxicity and dosing, make questions about when to begin ARVs and optimal sequencing of ARV therapy important to now address. Additional aims will leverage our combined large sample size and duration of follow-up to focus on identifying uncommon adverse events from new HIV therapies, long-term issues such as development of malignancy and effects of aging on HIV therapeutic response, developing new methods for observational HIV research and using our combined specimen repositories for pharmacogenetic and other transitional research. Appropriately, our Aims are most relevant to North America;however, they will also be generalizable to other regions where HAART is available (i.e., Western Europe), and will inform future HIV practice as it evolves in transitional and developing regions.