ObjectiveThis is a comprehensive characteristic study of Kawasaki disease (KD) and Multi system inflammatory syndrome in children (MIS-C) in the Middle East that creates a formula to differentiate between the two.MethodsWe conducted a descriptive comparative study of KD and MIS-C in the United Arab Emirates. Retrospective MIS-C and KD cohorts were recruited between January 2017 until August 2021.We compared clinical and laboratory characteristics between both groups. Our data were compared with 87 patients with KD or MIS-C from the literature.ResultsWe report on123 patients. Sixty-seven (54%) met the criteria for KD (36 male, 43 Arab), and fifty-six (46%) met the criteria for MIS-C (28 male, 35 Arab). The median age was 2.2 years range (0.15–10.7) in the KD group and 7.3 years (0.7–15.2) in the MIS-C group (P < 0.001). The clinical features on admission showed an increase in gastrointestinal manifestations in MIS-C compared with KD (84% vs. 31%, P < 0.001). Laboratory tests on admission revealed a significant increase in the following tests in KD compared with MIS-C; white blood cells (mean 16.30 10(3)µcL vs. 11.56 10(3)µcL, P < 0.001), absolute neutrophils (mean 10.72 10(3)µcL vs. 8.21 10(3)µcL, P 0.008), absolute lymphocytes (mean 3.92 10(3)µcL vs. 2.59 10(3)µcL, P 0.003), erythrocyte sedimentation rate (mean 73 mm/hr vs. 51 mm/hr, P < 0.001) and platelets (median {390 10(3)µcL vs. 236 10(3)µcL, P < 0.001}). In contrast, procalcitonin and ferritin were increased in the MIS-C group (2.4 )ng/mL, 370 ng/mL; P<0.001). Cardiac dysfunction and admission to the pediatric intensive care unit were higher in MIS-C than in KD (21% vs. 8% and 33% vs. 7.5%, respectively, P < 0.001).ConclusionThis study showed vast similarities between KD and MIS-C, suggesting that they lie along the same clinical spectrum. However, there are several differences between the two disease entities suggesting that MIS-C most likely represents a new severe variant of KD. Based on our findings in this study, we created a formula to differentiate between KD and MIS-C.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12969-023-00834-7.