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The relationship between SARS-CoV-2 variants of concern (VOCs) and the occurrence and severity of MIS-C is unknown. We analyzed the dynamics of MIS-C in the Milan metropolitan area (Italy) during the COVID-19 pandemic, focusing on the epidemiologic trends and disease severity in relation to different VOCs in a single-center study. Fifty-seven MIS-C patients (mean 8.3\u2009\u00b1\u20093.8\u00a0years) admitted to the Pediatric Department of Buzzi Children\u2019s Hospital in Milan, Italy, between November 2020 and July 2022, were retrospectively included in the study. The SARS-CoV-2 variant was retrospectively identified from serological fingerprinting (profiles of serum antibodies targeting different variants of SARS-CoV-2 obtained by a label-free microarray biosensor) or by the variant of prevalence. Two main periods of MIS-C case accumulation were observed. The peak of MIS-C cases rate in December 2020 reached 0.6 cases per day, which is nearly double the rate observed in February 2022, despite the larger number of infected subjects. Although the WT variant exhibited a broader range of severity score values, the score distributions for the different variants do not show statistically relevant differences. <jats:italic>Conclusion<\/jats:italic>: The results clearly show a decrease in the incidence of MIS-C in relation to infections, but also support the concept that severity of MIS-C remained essentially unchanged across different virus variants, including Omicron. The course of MIS-C, once initiated, is independent from the characteristics of the triggering variants, although later variants may be considered less likely to induce MIS-C.\n<jats:table-wrap>\n              <jats:table>\n                <jats:tbody>\n                  <jats:tr>\n                    <jats:td align=\"left\" colspan=\"3\">What is known:\u2022 MIS-C is a rare systemic inflammatory disorder that arises as a post-infectious complication temporally related to SARS-CoV-2 infection.\u2022 Fluctuations in MIS-C incidence were observed throughout the pandemic, with the latest variants associated with a lower incidence.<\/jats:td>\n                  <\/jats:tr>\n                  <jats:tr>\n                    <jats:td align=\"left\" colspan=\"3\">What is new:\u2022 The SARS-CoV-2 variant of infection can be retrospectively confirmed by serum antibody fingerprinting using a label-free microarray biosensor.\u2022 Despite the decreasing incidence, MIS-C severity has remained essentially unchanged across SARS-CoV-2 variants.<\/jats:td>\n                  <\/jats:tr>\n                <\/jats:tbody>\n              <\/jats:table>\n            <\/jats:table-wrap>\n          <\/jats:p>","DOI":"10.1007\/s00431-025-06153-1","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T06:40:49Z","timestamp":1746600049000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dynamics of Multisystem Inflammatory Syndrome in Children (MIS-C) associated to COVID-19: steady severity despite declining cases and new SARS-CoV-2 variants\u2014a single-center cohort study"],"prefix":"10.1007","volume":"184","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-4019","authenticated-orcid":false,"given":"Thomas","family":"Carzaniga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2137-5974","authenticated-orcid":false,"given":"Valeria","family":"Calcaterra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5049-1819","authenticated-orcid":false,"given":"Luca","family":"Casiraghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1677-1729","authenticated-orcid":false,"given":"Tommaso","family":"Inzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4603-396X","authenticated-orcid":false,"given":"Stephana","family":"Carelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3331-2815","authenticated-orcid":false,"given":"Gabriele","family":"Del Castillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5945-5710","authenticated-orcid":false,"given":"Danilo","family":"Cereda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2795-9874","authenticated-orcid":false,"given":"Gianvincenzo","family":"Zuccotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5010-0278","authenticated-orcid":false,"given":"Marco","family":"Buscaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"6153_CR1","doi-asserted-by":"publisher","unstructured":"Davies P, Evans C, Kanthimathinathan HK, et al. 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