BACKGROUND: The clinical manifestations and natural history of severe acute respiratory distress syndrome coronavirus 2 (SARS-Cov-2) related Multisystem Inflammatory Syndrome in Children (MIS-C) are poorly defined. Using a systematic review of individual cases and case series and collating elements of the clinical course, the objective of this study was to provide a detailed clinical description and natural history of MIS-C. METHODS: Case reports and series of MIS-C were recovered from repeated MEDLINE searches, a single EMBASE search and table of contents reviews of major general medicine and pediatric journals performed between June 3 and July 23, 2020. Fever, evidence of inflammation, and evidence of organ dysfunction were required for inclusion. RESULTS: MEDLINE and EMBASE searches produced 129 articles and 10 articles were identified from journal contents or article bibliographies; 16 reports describing 505 children with MIS-C comprise this review. Thirty- two children (14.7%) had negative results for SARS-Cov-2 by nucleic acid and/or antibody testing. The weighted median age was 9 years (6 months to 20 years). Clinical findings included fever (100%), gastrointestinal symptoms (88.0%), rash (59.2%), conjunctivitis (50.0%), chelitis/ "strawberry tongue" (55.7%) or extremity edema/erythema (47.5%). Median serum CRP, ferritin, fibrinogen and D dimer concentrations were above the normal range. Intravenous gammaglobulin (78.1%) and methylprednisolone/prednisone(57.6%) were the most common therapeutic interventions ; immunomodulation was used in 24.3% of cases. Myocardial dysfunction requiring ionotropic support (57.4%) plus extracorporeal membrane oxygenation (5.3%), respiratory distress requiring mechanical ventilation (26.1%), and acute kidney injury (11.9%) were the major complications; anticoagulation was used commonly (54.4%) but thrombotic events occurred rarely (3.5%). Seven (1.4%) children died. CONCLUSIONS: MIS-C following SARS-Cov-2 infection frequently presents with gastrointestinal complaints and/or rash; conjunctivitis, chelitis and/or extremity changes also occur frequently. Serious complications occur frequently and respond to aggressive supportive therapy.