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Context: The highly infectious Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused large-scale transmission from Dec 2022 to Feb 2023 in China. After this event, a remarkable surge of influenza A (Flu A) occurred from March to May 2023, especially in pediatric patients., Objectives: This study aimed to investigate the differences between pediatric patients infected with COVID-19 Omicron and Flu A virus., Methods: A total of 1,063 hospitalized children who admitted into two tertiary general hospital of Guangdong province of China were included. Medical records were compared retrospectively in these patients during the pandemic periods of SARS-CoV-2 omicron and Flu A., Results: A total of 592 Patients with Flu A were mostly preschool and school-aged (>3y, 76.0%), they showed higher ratio of high fever (≥39°C), cough, rhinorrhea, and vomiting than patients with SARS-CoV-2 omicron. Most of the 471 Omicron patients were young children (0-3y, 74.5%) and had more poor appetite and dyspnea symptom. Benign acute children myositis (BACM) was only observed in patients with Flu A, and a significant male predominance. Multisystem inflammatory syndrome in children (MIS-C) was only found in patients with SARS-CoV-2 Omicron. Compared to the SARS-CoV-2 Omicron group, for both age groups (0-3 years and > 3 years), the Flu A group showed significantly reduced lymphocyte (Lym) counts ( P < 0.001), and elevated levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatinine kinase-MB (CK-MB) in laboratory indexes (all P < 0.001). Additionally, it was found that more children hospitalized with COVID-19 had increased C-reactive protein (CRP) levels compared to those with Flu A., Conclusion: Influenza A infections have notably surged in children, coinciding with the relaxation of COVID-19 related social restrictions. During the epidemic periods of Omicron and Flu A virus infection, different clinical and laboratory characteristics were observed in hospitalized children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Chen, Zhang, Wu, Xie, Guan, Yang, Cai, Wen and Yang.)