The pathologic mechanisms causing Multisystem 38 Inflammatory Syndrome in Children (MIS-C) are not yet known; we sought to use high throughput proteomics to uncover signatures of dysregulation suggestive of pathophysiology fo this condition. MIS-C is a major complication of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. We performed a comprehensive analysis of more than 1400 proteins in the plasma proteome of children with SARS-CoV-2 and MIS-C.