Key PointsQuestionAre multisystem inflammatory syndrome in children (MIS-C) and COVID-19 in children associated with alterations in complement expression and function?FindingsIn this cross-sectional study with 145 participants, MIS-C and COVID-19 were associated with higher levels of complement components, activation products, and regulators. Additionally, complement levels pretreatment were found to be potential biomarkers of disease severity in MIS-C and COVID-19.MeaningThe findings of this study suggest that complement activation was associated with the pathogenesis of MIS-C and acute COVID-19 and is a potential biomarker of disease severity.