Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host range determinant since it mediates virus binding to host-specific cellular receptors 1–3 . Here, we therefore assessed the molecular changes in HA that would allow an H5 HA-possessing virus to transmit among mammals. We identified a reassortant virus with H5 HA possessing four mutations in a 2009 pandemic H1N1 virus backbone capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but it was not highly pathogenic and did not cause mortality. These results suggest that H5 HA can convert to an HA that supports efficient viral transmission in mammals. However, we do not know whether the four mutations in the H5 HA identified in this study would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral genes may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avian-human reassortant viruses as tested here, may emerge. Our findings emphasize the need for pandemic preparedness for H5 HA-possessing viruses and will help individuals conducting surveillance in regions with circulating H5N1 viruses to recognize key residues that predict the pandemic potential of isolates, which will inform the development, production, and distribution of effective countermeasures.