Since its initial detection, the SARS-CoV-2 Omicron sublineage BA.2 has been spreading rapidly worldwide. The aims of this study were to describe the first 284 patients infected with the Omicron BA.2 variant of concern (VOC) in the Apulia region of southern Italy and to assess the differences in the demographic and clinical characteristics of patients infected with the SARS-CoV-2 BA.1 and BA.2 variants. The demographic characteristics of patients, as well as information about symptoms, vaccinations and hospitalizations for COVID-19, were collected. A subset of samples from patients infected with the BA.2 variant was subjected to whole-genome sequencing. The characteristics of the first 284 patients infected with Omicron BA.2 and the first 175 patients infected with Omicron BA.1 were compared. The proportion of patients infected with the BA.2 variant rapidly increased, from 0.5% during the third week of 2022 to 29.6% during the tenth week of 2022. Ten isolates (out of 34 BA.2 isolates) contain the substitutional mutation, H78K in ORF3a, and four isolates include two mutations, A2909V in ORF1a and L140F in ORDF3a. Compared with patients infected with BA.1, those infected with BA.2 were more likely to be symptomatic and booster-vaccinated, and showed a shorter time from the last dose of vaccine to infection. The high transmissibility and immune-evasive properties of Omicron BA.2, which will become the leading SARS-CoV-2 VOC, suggest that short-term public health measures should not be discontinued in Italy.