The SARS-CoV-2 pandemic continues to spread worldwide, generating a high impact on healthcare systems. The aim of the study was to examine the epidemiological burden of SARS-CoV-2 reinfections and to identify potential related risk factors. A retrospective observational study was conducted in Liguria Region, combining data from National Vaccines Registry and Regional Chronic Condition Data Warehouse. In the study period (September 2021 to May 2022), 335,117 cases of SARS-CoV-2 infection were recorded in Liguria, of which 15,715 were reinfected once. During the Omicron phase (which predominated from 3 January 2022), the risk of reinfection was 4.89 times higher (p p p p p p p p = 0.0003; OR of 1.09, p p = 0.0056; OR of 1.78, p p = 0.0205). Estimating the epidemiological burden of SARS-CoV-2 reinfections and the role played by risk factors in reinfections is relevant for identifying risk-based preventive strategies in a pandemic context characterized by a high circulation of the virus and a high rate of pathogen mutations.