The study assesses the pandemic potential of a highly pathogenic H5N1 virus isolated from mink, which has recently spread to seals and humans. Using the ferret model, the researchers found that the mink-derived H5N1 virus transmitted directly to 75% of exposed ferrets and through the air to 37.5% of contacts. Sequence analysis revealed no mutations associated with transmission. The virus had a low infectious dose and remained virulent at low doses. The virus carried the PB2 T271A mutation, which was associated with reduced mortality and airborne transmission when reversed. This is the first report of a clade 2.3.4.4b H5N1 virus exhibiting direct contact and airborne transmissibility in ferrets, highlighting the need for continued efforts to control outbreaks and monitor viral evolution.The study assesses the pandemic potential of a highly pathogenic H5N1 virus isolated from mink, which has recently spread to seals and humans. Using the ferret model, the researchers found that the mink-derived H5N1 virus transmitted directly to 75% of exposed ferrets and through the air to 37.5% of contacts. Sequence analysis revealed no mutations associated with transmission. The virus had a low infectious dose and remained virulent at low doses. The virus carried the PB2 T271A mutation, which was associated with reduced mortality and airborne transmission when reversed. This is the first report of a clade 2.3.4.4b H5N1 virus exhibiting direct contact and airborne transmissibility in ferrets, highlighting the need for continued efforts to control outbreaks and monitor viral evolution.