Phylogenetic analysis of six SARS-CoV-2 genomes collected from the Comoros islands confirmed local circulation of the 501Y.V2 variant of concern during the country’s first major SARS-CoV-2 wave in January 2021. These findings demonstrate the importance of SARS-CoV-2 genomic surveillance and have implications for ongoing COVID-19 control strategies on the islands. Article summary line Circulation of SARS-CoV-2 501Y.V2 variant of concern in the Comoros Islands during a major COVID-19 infection wave in January 2021