We describe that acute MIS-C is characterized by elevations of C1s-C1-inhibitor complex, C4a and C4d levels, activation markers of the C1 complex and of the common section of the classical and lectin pathways, by increased Bb and C3a concentrations, indicating amplification via the alternative pathway and activation of the central component C3, and finally, by elevation of sC5b-9, the activation product of the potentially cell-damaging terminal pathway. Here, C1S is linked to COVID-19–associated multisystem inflammatory syndrome in children.