Paediatric COVID-19 (pCOVID-19) is rarely severe, but a small minority of children infected with SARS-CoV-2 develop a multisystem inflammatory syndrome (MIS-C). This study describes distinct immunological signatures in pCOVID-19 versus MIS-C. While pCOVID-19 was characterized by robust type I interferon (IFN) responses, MIS-C was associated with IFNγ-dependent and NF-κB-dependent signatures, activation of extracellular matrix and increased levels of circulating SARS-CoV-2 Spike protein. The study also confirmed an earlier report linking MIS-C with the combination of the HLA-A*02, HLA-B*35 and HLA-C*04 alleles. Understanding the unique immunopathology of pCOVID-19 compared with MIS-C may guide better therapies for children infected with SARS-CoV-2.