Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. We quantified anti–type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections. Circulating anti–IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti–IFN-α2 autoantibodies exceeding the assay’s positive control. Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti–IFN-α2 antibodies. Anti–IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa–light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient’s peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. High levels of anti–IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.