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This study aimed to analyze the differences in severity and clinical characteristics of COVID-19 in infants hospitalized in Poland in 2021, when the dominance of variants of concern (VOCs) alpha and delta was reported, compared to 2020, when original (wild) SARS-CoV-2 was dominant (III–IV vs. I–II waves of the pandemic, respectively). In addition, the influence of the presence of comorbidities on the clinical course of COVID-19 in infants was studied. This multicenter study, based on the pediatric part of the national SARSTer database (SARSTer-PED), included 940 infants with COVID-19 diagnosed between March 1, 2020, and December 31, 2021, from 13 Polish inpatient centers. An electronic questionnaire, which addressed epidemiological and clinical data, was used. The number of hospitalized infants was significantly higher in 2021 than in 2020 (651 vs. 289, respectively). The analysis showed similar lengths of infant hospitalization in 2020 and 2021, but significantly more children were hospitalized for more than 7 days in 2020 (p < 0.009). In both analyzed periods, the most common route of infection for infants was household contact. There was an increase in the percentage of comorbidities, especially prematurity, in children hospitalized in 2021 compared to 2020. Among the clinical manifestations, fever was predominant among children hospitalized in 2021 and 2020. Cough, runny nose, and loss of appetite were significantly more frequently observed in 2021 (p < 0.0001). Severe and critical conditions were significantly more common among children with comorbidities. More infants were hospitalized during the period of VOCs dominance, especially the delta variant, compared to the period of wild strain dominance, even though indications for hospitalization did not include asymptomatic patients during that period. The course of COVID-19 was mostly mild, characterized mainly by fever and respiratory symptoms. Comorbidities, particularly from the cardiovascular system and prematurity, were associated with a more severe course of the disease in infants.