Background SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. Methods To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression both at the bulk and single cell levels. Findings The most severe forms of multisystem inflammatory syndrome in children related to SARS-CoV-2 (MIS-C), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κB activity, TNF-α signaling, associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. Conclusions These results provide potential for a better understanding of disease pathophysiology. Funding Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Intérieur”, grant ANR-10-LABX-69-01, ANR-flash Covid19 “AIROCovid” and “CoVarImm”), Institut National de la Santé et de la Recherche Médicale (INSERM) and the “URGENCE COVID-19” fundraising campaign of Institut Pasteur

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