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Abstractintroduction: This is the 39 th Annual Report of America's Poison Centers' National Poison Data System (NPDS). As of 1 January, 2021, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 4.87 [4.38, 8.62] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system., Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure., Results: In 2021, 2,851,166 closed encounters were logged by NPDS: 2,080,917 human exposures, 62,189 animal exposures, 703,086 information requests, 4,920 human confirmed nonexposures, and 54 animal confirmed nonexposures. Total encounters showed a 14.0% decrease from 2020, and human exposure cases decreased by 2.22%, while health care facility (HCF) human exposure cases increased by 7.20%. All information requests decreased by 37.0%, medication identification (Drug ID) requests decreased by 20.8%, and medical information requests showed a 61.1% decrease, although these remain about 13-fold higher than before the COVID-19 pandemic. Drug Information requests showed a 146% increase, reflecting COVID-19 vaccine calls to PCs. Human exposures with less serious outcomes have decreased 1.80% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.56% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (11.2%), household cleaning substances (7.49%), cosmetics/personal care products (5.88%), antidepressants (5.61%), and sedatives/hypnotics/antipsychotics (4.73%). As a class, antidepressant exposures increased most rapidly, by 1,663 cases/year (5.30%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (10.8%), household cleaning substances (10.7%), analgesics (8.16%), dietary supplements/herbals/homeopathic (7.00%), and foreign bodies/toys/miscellaneous (6.51%). Drug identification requests comprised 3.64% of all information contacts. NPDS documented 4,497 human exposures resulting in death; 3,809 (84.7%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory)., Conclusions: These data support the continued value of PC expertise and the need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.