The novel coronavirus SARS-CoV-2 is the cause of the COVID-19 pandemic which rapidly spread worldwide in early 2020. The severity of symptoms of COVID-19 disease, especially among the elderly and high-risk population groups, as well as the complications of the disease, forced the immediate implementation of preventive and protection measures. Moreover, vaccination programs were focused on cooping the virus transmission and spread of the virus in the general population, as well as on the immunization of the community against COVID-19 infection. The circulation of SARS-CoV-2 globally still appears and, as reported to FluNet, was around 10% by the end of February 2024, while the number of new cases and the number of new deaths have decreased. From December 2019, when the first outbreak of the virus was detected in Wuhan, China, until now, SARS-CoV-2 has undergone numerous mutations that have had a major impact on its pathogenesis during the COVID-19 pandemic. Among the SARS-CoV-2 variants and mutations, some are geographically identified, such as D614G, B.1.1.7 in the United Kingdom, B.1.1.28 in Brazil, CAL.20C in Southern California, B.1.351 in South Africa, while B.1.617 and B.1.1.529 have been reported worldwide. The main reason for the identification of SARS-CoV-2 variants and mutations is to investigate any correlation between new mutations and their impact on vaccine efficacy, despite the reported high vaccination rates of the vaccines that were implemented worldwide. The aim of this study is to investigate the correlations between SARS-CoV-2 S-gene target mutations with demographic characteristics, vaccination, hospitalization, and history of previous COVID-19 disease, in patients that were admitted to “Agios Panteleimon” General Hospital of Nikea, Piraeus, Greece, between August 2023 and January 2024.