A highly pathogenic avian influenza A(H5N1) outbreak was reported in Argentina in August 2023, affecting sea lions, fur seals, and terns. The virus, belonging to clade 2.3.4.4b, was detected in sea lions along the Argentine coast, with the most severe outbreak at Punta Bermeja, where over 800 sea lions died. The virus was also found in a South American tern and a fur seal. Full-genome sequencing revealed that the virus was closely related to strains from Chile and Peru, suggesting a separate introduction into Argentina. The virus showed mammalian adaptation mutations, such as Q591K and D701N in the polymerase basic 2 gene, which enhance pathogenicity in mammals. These mutations were also present in a human H5N1 virus from Chile, indicating potential cross-species transmission. Phylogenetic analysis showed that the viruses from Punta Bermeja did not cluster with those from birds in Uruguay, Brazil, or Bird Island, suggesting separate transmission routes. The study highlights the risk of H5N1 viruses to public health due to their ability to infect both mammals and birds. The outbreak underscores the need for continued surveillance and research on the spread and adaptation of avian influenza viruses in wildlife and humans.A highly pathogenic avian influenza A(H5N1) outbreak was reported in Argentina in August 2023, affecting sea lions, fur seals, and terns. The virus, belonging to clade 2.3.4.4b, was detected in sea lions along the Argentine coast, with the most severe outbreak at Punta Bermeja, where over 800 sea lions died. The virus was also found in a South American tern and a fur seal. Full-genome sequencing revealed that the virus was closely related to strains from Chile and Peru, suggesting a separate introduction into Argentina. The virus showed mammalian adaptation mutations, such as Q591K and D701N in the polymerase basic 2 gene, which enhance pathogenicity in mammals. These mutations were also present in a human H5N1 virus from Chile, indicating potential cross-species transmission. Phylogenetic analysis showed that the viruses from Punta Bermeja did not cluster with those from birds in Uruguay, Brazil, or Bird Island, suggesting separate transmission routes. The study highlights the risk of H5N1 viruses to public health due to their ability to infect both mammals and birds. The outbreak underscores the need for continued surveillance and research on the spread and adaptation of avian influenza viruses in wildlife and humans.