BACKGROUND: The infection with SARS-CoV-2 in children usually manifests as a mild respiratory tract infection. The aim of this study was to evaluate the severity, outcome and vaccination status in children hospitalized for COVID-19 in a single center during two pandemic waves determined by different SARS-CoV-2 variants of concern (VOCs). METHODS: A retrospective study on 656 consecutive pediatric patients was performed from September 1, 2021, to April 30, 2023. The study interval was divided into waves, according to official data on the circulation of Delta and Omicron VOCs. Data collected included sex, age, comorbidities, date of diagnosis, duration of hospitalization, vaccination status, clinical outcome. RESULTS: The Delta group consisted of 234 children with a mean age of approximately 9 years, while the Omicron group included 422 children with a mean age of around 2.5 years. Most cases were mild, although in the Omicron wave the hospitalization rate was higher and 41.7% of the cases were medium in severity. The presence of comorbidities was not linked to an increase in severity. Vaccination rates were low in both groups, with a mean of 4% for the total of eligible patients. CONCLUSION: This pioneering study highlights the nature of COVID-19 in children, focusing on both clinical aspects and public health issues.