A novel highly pathogenic avian influenza (HPAI) H5N8 virus, first detected in January 2014 in poultry and wild birds in South Korea, has spread throughout Asia and Europe and caused outbreaks in Canada and the United States by the end of the year. The spread of H5N8 and the novel reassortant viruses, H5N2 and H5N1 (H5Nx), in domestic poultry across multiple states in the United States pose a potential public health risk. To evaluate the potential of cross-species infection, we determined the pathogenicity and transmissibility of two Asian-origin H5Nx viruses in mammalian animal models. The newly isolated H5N2 and H5N8 viruses were able to cause severe disease in mice only at high doses. Both viruses replicated efficiently in the upper and lower respiratory tracts of ferrets; however, the clinical symptoms were generally mild, and there was no evidence of systemic dissemination of virus to multiple organs. Moreover, these influenza H5Nx viruses lacked the ability to transmit between ferrets in a direct contact setting. We further assessed viral replication kinetics of the novel H5Nx viruses in a human bronchial epithelium cell line, Calu-3. Both H5Nx viruses replicated to a level comparable to a human seasonal H1N1 virus, but significantly lower than a virulent Asian-lineage H5N1 HPAI virus. Although the recently isolated H5N2 and H5N8 viruses displayed moderate pathogenicity in mammalian models, their ability to rapidly spread among avian species, reassort, and generate novel strains underscores the need for continued risk assessment in mammals. O n 16 December 2014, the U.S. Department of Agriculture (USDA) confirmed the presence of a novel highly pathogenic avian influenza (HPAI) H5N8 virus in a captive gyrfalcon and H5N2 virus in a northern pintail duck from Whatcom County, Washington (1). This represented the first appearance of HPAI H5 virus in the United States since 2004 when H5N2 subtype virus was confirmed on a poultry farm in Texas (2). HPAI H5N8 viruses were first reported in duck farms in eastern China in 2010, and in early 2014 a novel reassortant H5N8 virus was detected in poultry in South Korea (3-5). The novel virus, belonging to Eurasian lineage clade 2.3.4.4 (formerly clade 2.3.4.6), subsequently spread to China, Japan, and five countries in Europe (6, 7). In November 2014, the virus was detected on chicken and turkey farms in British Columbia, Canada, followed by Washington State, USA, the following month (8). The novel H5N8 viruses continue to spread to multiple regions and have been found in three North America flyways (Pacific, Central, and Mississippi), where wild-bird migrations occur (USDA, Animal and Plant Health Inspection Service [http://www.aphis.usda.gov]). In addition, genetic reassortment with circulating North American avian influenza viruses has resulted in novel HPAI viruses, including H5N2 and H5N1 subtypes. These novel reassortant viruses carry a Eurasian-origin hemagglutinin (HA) gene genetically related to H5N8 viruses detected in South Korea in 2014 and the neura...