Background: Highly pathogenic avian influenza (HPAI) H5 viruses of the A/Goose/Guangdong/1/1996 (GsGd) lineage pose significant global risks to wildlife, domestic animals, and humans. Recent cross-species transmission events to mammals, including humans, highlight this risk. Critical determinants for cross-species and intra-species transmission include the ability to attach to and replicate in respiratory epithelial cells. Although these factors have been studied for HPAI H5N1 viruses in the past, limited studies are available for currently circulating strains. Methods: We compared level of adaptation to human respiratory tract of a HPAI H5N1 clade 2.3.4.4b (H5N1.2022) virus with those of well characterized HPAI H5N1 clade 2.1.3.2 (H5N1.2005) and seasonal H3N2.2003 viruses by three methods. First, we compared pattern of virus attachment by virus histochemistry. Second, we compared efficiency of infection and replication, as well as innate immune responses in human respiratory epithelium in vitro. Lastly, we compared polymerase complex activity in a minigenome assay. Findings: The H5N1.2022 virus attached more abundantly to and replicated more efficiently in cells of the human respiratory tract compared to H5N1.2005 and H3N2.2003 viruses. This increased replication was not associated with an increased polymerase activity of H5N1.2022 virus compared to H3N2.2003 virus. The efficient replication of H5N1.2022 virus infection induced a robust innate immune response almost comparable to H3N2.2003. Interpretation: The pattern of virus attachment and replication efficiency of a HPAI H5N1.2022 virus resembled that of H3N2.2003 virus more closely than a HPAI H5N12005. This could contribute to an increased risk for both human infection and virus adaptations to humans.