© 2021 Cambridge University Press. All rights reserved.Introduction The aim of this study was to make the differential diagnosis between acute appendicitis and multisystem inflammatory syndrome in children (MIS-C) for patients presenting with the complaint of acute abdominal pain (AAP) and to identify the determining factors for the diagnosis of MIS-C. Materials and Methods Eighty-one children presenting with AAP/suspected AAP were evaluated. Of these, 24 (29.6%) were included in the MIS-C group (MIS-C/g) and 57 were included in the suspected appendicitis group (S-A/g), which consisted of two subgroups: appendicitis group (A/g) and control observation group (CO/g). Results Comparing MIS-C/g, A/g, and CO/g, duration of abdominal pain (2.4, 1.5, 1.8 days), high-grade fever (38.8, 36.7, 37°C), severe vomiting, and severe diarrhea were higher in MIS-C/g. Lymphocytes count (LC) was lower, while values of C-reactive protein (CRP), ferritin, and coagulopathy were higher in MIS-C/g (p < 0.05). The optimal cutoffs for the duration of abdominal pain was 2.5 days; the duration of fever, 1.5 days; peak value of fever, 39°C; neutrophil count, 13,225 × 1,000 cell/μMoL; LC, 600 × 1,000 cell/μMoL; ferritin, 233 μg/L; and D-dimer, 16.4 mg/L (p < 0.05). The optimal cutoff for CRP was 130 mg/L (sensitivity 88.9, specificity 100%, positive predictive value 100%, NPV, negative predictive value 92.5%, p < 0.001). All patients in MIS-C/g tested positive by serology by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Conclusion The duration of abdominal pain, presence of high-grade and prolonged fever, and evaluation of hemogram in terms of high neutrophil count and low LC exhibit high sensitivity and negative predictive value for MIS-C presenting with AAP. In case of doubt, inflammatory markers such as CRP, ferritin, D-dimer, and serology for SARS-CoV-2 should be studied to confirm the diagnosis.