Three critically ill or fatal avian influenza A(H5N1) human infections have been reported in North America since November 2024. Notably, all were infected with genotype D1.1 instead of B3.13, the dominant genotype before November 2024. Here, we demonstrated that D1.1 could replicate to higher titers in human nasal and airway organoid-derived transwell monolayers from 6 donors. D1.1 exhibited a better binding to α2,3- and α2,6-linked SA than B3.13. No significant differences in most inflammatory or antiviral cytokines/chemokines was observed. These observations suggest that D1.1 is better adapted to both the upper and lower human respiratory tract epithelium than B3.13.