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Background Multisystem inflammatory syndrome in adults (MIS-A) is a severe condition temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods In this retrospective cohort study, we applied the US Centers for Disease Control and Prevention (CDC) case definition to identify diagnosed and undiagnosed MIS-A cases among adults discharged during April 2020–January 2021 from 4 Atlanta, Georgia hospitals affiliated with a single medical center. Non–MIS-A coronavirus disease 2019 (COVID-19) hospitalizations were identified using International Classification of Diseases, Tenth Revision, Clinical Modification encounter code U07.1. We calculated the ratio of MIS-A to COVID-19 hospitalizations, compared demographic characteristics of the 2 cohorts, and described clinical characteristics of MIS-A patients. Results We identified 11 MIS-A cases, none of which were diagnosed by the treatment team, and 5755 COVID-19 hospitalizations (ratio 1:523). Compared with patients with COVID-19, patients with MIS-A were more likely to be younger than 50 years (72.7% vs 26.1%, P <.01) and to be non-Hispanic Black (81.8% vs 50.0%, P =.04). Ten patients with MIS-A (90.9%) had at least 1 underlying medical condition. Two MIS-A patients (18.2%) had a previous episode of laboratory-confirmed COVID-19, occurring 37 and 55 days prior to admission. All MIS-A patients developed left ventricular systolic dysfunction. None had documented mucocutaneous involvement. All required intensive care, all received systemic corticosteroids, 8 (72.7%) required mechanical ventilation, 2 (18.2%) required mechanical cardiovascular circulatory support, and none received intravenous immunoglobulin. Two (18.2%) died or were discharged to hospice. Conclusions MIS-A is a severe but likely underrecognized complication of SARS-CoV-2 infection. Improved recognition of MIS-A is needed to quantify its burden and identify populations at highest risk. [ABSTRACT FROM AUTHOR]