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Background: Due to increasing proportion of asymptomatic severe acute respiratory syndrome coronavirus 2 infections and previously reported overlapping features, the distinction between Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) remains challenging. Statistical differentiation models for clinical guidance are scarce and should focus on cardiac involvement, as differences in cardiac involvement might serve as a potential clinical finding for early recognition of MIS-C. Methods: We retrospectively analyzed 298 MIS-C and KD cases treated during the 22-year period (from 2003 to 2024), and compared demographic, clinical, laboratory, ultrasound and cardiac findings. A multivariable differentiation model based on clinical, laboratory, ultrasound and cardiac features was developed for distinguishing KD/MIS-C cases. Results: Of 298 cases, 162 (54.4%) were diagnosed with KD. MIS-C patients were significantly older (109.1 vs. 45.5 months, P < 0.001) and had higher admission rates to the intensive care unit (52.2% vs. 29.0%, P < 0.001). Rash ( P < 0.001), conjunctivitis ( P = 0.013), mucosal ( P < 0.001) and extremity changes ( P < 0.001) were more common in KD, while gastrointestinal symptoms were more common in MIS-C ( P < 0.001). MIS-C patients also had higher C-reactive protein values ( P < 0.001). Pericarditis, congestive heart failure and mitral regurgitation ( P < 0.001) were more common in MIS-C patients. Based on our model, older age, higher C-reactive protein values, gastrointestinal symptoms, hyponatremia, presence of ascites and mitral regurgitation were predictive of MIS-C. Conclusions: Our model is the first to report mitral regurgitation as a potential diagnostic hallmark for MIS-C. Comprehensive clinical, laboratory and ultrasound evaluation of patients with overlapping features of KD/MIS-C improves diagnostic yield. Future models should increase sample size and focus on external model validation.