The study investigates the susceptibility of swine to highly pathogenic avian influenza (HPAI) viruses belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade, which has caused significant outbreaks in poultry, wild birds, and mammals across North America since 2022. The research assesses the pathogenesis and transmission of four strains of HPAI H5N1 clade 2.3.4.4b in pigs using a pathogenesis and transmission model. All strains replicated in the lungs of pigs, causing lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission were observed only with mammalian isolates containing the PB2 E627K mutation, which is associated with mammalian adaptation. The study highlights the potential for reassortment between HPAI viruses and endemic swine influenza viruses, increasing the risk of human infection and adaptation. The findings emphasize the need for continued surveillance and biosecurity measures to prevent the spread of HPAI viruses in swine populations.The study investigates the susceptibility of swine to highly pathogenic avian influenza (HPAI) viruses belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade, which has caused significant outbreaks in poultry, wild birds, and mammals across North America since 2022. The research assesses the pathogenesis and transmission of four strains of HPAI H5N1 clade 2.3.4.4b in pigs using a pathogenesis and transmission model. All strains replicated in the lungs of pigs, causing lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission were observed only with mammalian isolates containing the PB2 E627K mutation, which is associated with mammalian adaptation. The study highlights the potential for reassortment between HPAI viruses and endemic swine influenza viruses, increasing the risk of human infection and adaptation. The findings emphasize the need for continued surveillance and biosecurity measures to prevent the spread of HPAI viruses in swine populations.