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Many African countries, representing the origin of the majority of refugees, asylum-seekers, and other migrants, toward regions bordering on the Mediterranean area, are experiencing sustained local transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sicily is one of the main entry gates of migrants crossing into Europe. We conducted a pilot study, based on the full-genome sequencing of SARS-CoV-2 strains isolated from migrants coming to Sicily by crossing the Mediterranean Sea, with the aim to investigate the viral genome polymorphism and to describe their genetic variations and the phylogenetic relationships. On June 21, a nongovernmental organization vessel rescued 210 migrants crossing the Mediterranean Sea from Libya to Sicily. Of them, 13.4% tested positive for SARS-CoV-2. Eighteen whole genome sequences were obtained to explore viral genetic variability. All but one of the sequences clustered with other viral African strains within the lineage A, whereas only one intermixed among B.1 lineage genomes. Our findings documented that most of the investigated migrants acquired SARS-CoV-2 infection before landing in Sicily. However, SARS-CoV-2 transmission during travel or in overcrowded Libyan immigrant camps and/or illegal transport boats could not be ruled out. SARS-CoV-2 molecular surveillance on migrants arriving in Europe through the Sicilian gate may improve the knowledge of global SARS-CoV-2 transmission dynamic also in light of the emergence of new variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tramuto, Reale, Lo Presti, Vitale, Pulvirenti, Rezza, Vitale, Purpari, Maida, Zichichi, Scibetta, Mazzucco and Stefanelli.)