Highly pathogenic avian influenza (HPAI) A(H5N1) viruses belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected poultry, wild birds, and mammals across North America since 2022. These viruses have the potential to cross species barriers and cause pandemics. The study assessed the susceptibility of swine to these HPAI strains, finding that all strains replicated in the lungs of pigs and caused lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission were only observed with mammalian isolates. Mammalian adaptation and reassortment may increase the risk for incursion and transmission of HPAI viruses in swine. Influenza A viruses (IAV) of avian and swine origin have caused 5 pandemics in the previous 2 centuries. Aquatic avian populations, the primary reservoir for IAV, harbor numerous virus subtypes (H1-16), to which mammals have minimal preexisting immunity. Among those subtypes, H5 avian influenza virus infections have been documented in domestic poultry, humans, marine mammals, and swine. Over the past decade, H5NX HPAI viruses belonging to the goose/Guangdong (Gs/GD) 2.3.4.4 hemagglutinin (HA) phylogenetic clade have caused infections in wild birds and poultry, resulting in major mortality events and spread to >84 countries. These viruses have been recognized as a panzootic. Evidence exists of enzootic HPAI virus maintenance in Europe, further signifying a paradigm shift in the biology of HPAI. Since February 2022, HPAI H5N1 clade 2.3.4.4b virus originating from a trans-Atlantic incursion has caused outbreaks across North America, resulting in >77 million poultry deaths, extensive deaths in wild bird species, and unprecedented disease in wild mammals. The transcontinental circulation of clade 2.3.4.4b viruses within bird populations continues to enable reassortment with low pathogenicity avian influenza (LPAI) viruses and resulted in the emergence of numerous genotypes of potentially different phenotypes. Mammalian adaptation of HPAI is a multigenic trait, and the genetic changes necessary for H5N1 strains to adapt to swine and acquire efficient and sustained transmissibility are poorly understood. However, swine-adapted IAV have a propensity for evolution through polymerase errors and reassortment, followed by spread of mutated or reassorted strains through contact among densely housed commercial pigs and pig transport. If an avian IAV strain, such as H5Nx 2.3.4.4b, successfully infected domestic swine, pig-to-pig transmissionHighly pathogenic avian influenza (HPAI) A(H5N1) viruses belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected poultry, wild birds, and mammals across North America since 2022. These viruses have the potential to cross species barriers and cause pandemics. The study assessed the susceptibility of swine to these HPAI strains, finding that all strains replicated in the lungs of pigs and caused lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission were only observed with mammalian isolates. Mammalian adaptation and reassortment may increase the risk for incursion and transmission of HPAI viruses in swine. Influenza A viruses (IAV) of avian and swine origin have caused 5 pandemics in the previous 2 centuries. Aquatic avian populations, the primary reservoir for IAV, harbor numerous virus subtypes (H1-16), to which mammals have minimal preexisting immunity. Among those subtypes, H5 avian influenza virus infections have been documented in domestic poultry, humans, marine mammals, and swine. Over the past decade, H5NX HPAI viruses belonging to the goose/Guangdong (Gs/GD) 2.3.4.4 hemagglutinin (HA) phylogenetic clade have caused infections in wild birds and poultry, resulting in major mortality events and spread to >84 countries. These viruses have been recognized as a panzootic. Evidence exists of enzootic HPAI virus maintenance in Europe, further signifying a paradigm shift in the biology of HPAI. Since February 2022, HPAI H5N1 clade 2.3.4.4b virus originating from a trans-Atlantic incursion has caused outbreaks across North America, resulting in >77 million poultry deaths, extensive deaths in wild bird species, and unprecedented disease in wild mammals. The transcontinental circulation of clade 2.3.4.4b viruses within bird populations continues to enable reassortment with low pathogenicity avian influenza (LPAI) viruses and resulted in the emergence of numerous genotypes of potentially different phenotypes. Mammalian adaptation of HPAI is a multigenic trait, and the genetic changes necessary for H5N1 strains to adapt to swine and acquire efficient and sustained transmissibility are poorly understood. However, swine-adapted IAV have a propensity for evolution through polymerase errors and reassortment, followed by spread of mutated or reassorted strains through contact among densely housed commercial pigs and pig transport. If an avian IAV strain, such as H5Nx 2.3.4.4b, successfully infected domestic swine, pig-to-pig transmission