Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children. Display omitted •One third of 228 patients with Multisystem Inflammatory Syndrome in Children (MIS-C) presented with thrombocytopenia.•Hyperinflammation and elevated biomarkers associated with T-cell activation were observed in thrombocytopenic MIS-C patients.•Independent of disease severity, thrombocytopenic patients had reduced leukocytes and signs of liver injury as seen in  HLH.•No pathogenic variants in HLH genes were identified in any of the 62 MIS-C patients analyzed using whole-exome-sequencing.