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Abstract Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare complication, which develops within 3–6 weeks after SARS-CoV2 infection. The coronavirus disease 2019 (COVID-19) vaccine was firstly introduced in adults and adolescents and later in patients aged 5–11 years old. Although a reduced incidence of MIS-C and with less severe symptoms has been reported in vaccinated adolescents, there is little knowledge in children younger than 12 years of age. In addition, it is not understood whether MIS-C in vaccinated patients can be triggered by Covid19 vaccination or be secondary to a recent asymptomatic Sars-Cov2 infection. Case presentation We describe the case of a Caucasian 6-year-old girl, one month after double COVID-19 vaccination, who presented fever, acute abdominal pain, rash, pharyngotonsillitis, cheilitis, cervical lymphadenopathy without a prior detected Sars-Cov2 infection. She also had lymphopenia, increase in inflammatory markers, cardiac and pulmonary involvement. Therefore, we dosed both anti Sars-Cov2 Spike and Nucleocapsid antibodies, which were positive and allowed us to confirm the diagnosis of MIS-C. We promptly administered intravenous immunoglobulins and methylprednisone, resulting in the initial regression of fever. During the hospitalization, the child also developed pancreatitis and severe neurological involvement, including irritability, drowsiness, distal tremor, dyskinesia and buccal asymmetry with complete resolution after 2 months. After 3 months from the onset of the symptoms, she reported a transient loss of hair compatible with telogen effluvium. After 12 months of follow-up, she did not show any symptomatic sequelae. Conclusions This case raises the question of whether COVID-19 vaccination may be involved in the pathogenesis of MIS-C in children between the ages of 5 and 11 years old.