Since early 2022 the Omicron variant has rapidly spread worldwide, becoming the dominant variant to date. The study aimed to investigate the clinical and epidemiological characteristics of COVID-19 patients and to reconstruct the genomic epidemiology of main SARS-CoV-2 Omicron sub-lineages in Italy in 2022. 8,970 SARS-CoV-2 samples were studied, and phylogenetic analyses were focused on BA.1, BA.2 and BA.5 sub-variants. More than half of subjects received three doses of vaccine and experienced a reinfection. A significant larger proportion of unvaccinated subjects presented reinfection compared to vaccinated. Clusters presented a tMRCA between September-November 2021 (BA.1), November 2021-January 2022 (BA.2) and October 2021-May 2022 (BA.5). R e values showed the highest level between September-October, January-February 2022, and May 2022 for BA.1, BA.2 and BA.5, respectively. Limited number of studied variant sequences are included in clusters. The analyses dissect the epidemiological dynamics of Omicron sub-lineages in Italy over a period of great epidemiological changes in the COVID-19 epidemic. The spread rate of the studied variant exceeded its evolutionary rate. No single sub-lineage had sufficient time to differentiate into large clusters, but only into small and fragmented groups sharing the same recent ancestor. These analyses dissect the epidemiological dynamics of Omicron sub-lineages in Italy over a period of great epidemiological changes in the COVID-19 epidemic.