What is Known:

• Before our study, only two publications investigated the incidence of MIS-C regarding SARS-CoV-2 variants in Europe, one from Southeast England and another from Denmark.

What is New:

• To our knowledge, this is the first study investigating MIS-C incidence in Southern Europe, with the ability to recruit all MIS-C cases in a determined area and analyze the rate ratio for MIS-C among SARS-CoV-2 infections throughout variant periods.

• We found a lower rate ratio of MISC/infections with SARS-CoV-2 in the Omicron period for all age groups, including those not eligible for vaccination, suggesting that the variant could be the main factor for this shift in the MISC trend.