Key PointsQuestionDo autoantibodies targeting the heart play a role in the cardiac complications of SARS-CoV-2–associated multisystem inflammatory syndrome in children (MIS-C) or COVID-19 mRNA vaccination?FindingsThis diagnostic study including 20 children with MIS-C or COVID 19 vaccine–induced myocarditis and 21 adult and pediatric controls found no evidence of autoantibodies in serum of patients with MIS-C or vaccine-induced myocarditis binding donor cardiac tissue.MeaningThese results suggest that anticardiac autoantibodies are unlikely to play a role in the cardiac pathology seen in MIS-C or COVID-19 vaccine–induced myocarditis.