Since emerging in 2013, the avian-origin H7N9 influenza viruses have resulted in over 400 human infections leading to 115 deaths to date. Although the epidemiology differs from human highly pathogenic avian H5N1 influenza infections, there is a similar rapid progression to acute respiratory distress syndrome (ARDS). The aim of these studies was to compare the pathological and immunological characteristics of a panel of human H7N9 and H5N1 viruses in vitro and in vivo. Although there were similarities between particular H5N1 and H7N9 viruses, including association between lethal disease and spread to the alveolar spaces and kidney, there were also strain-specific differences. Both H5N1 and H7N9 viruses are capable of causing lethal infections, with mortality correlating most strongly with wider distribution of viral antigen in the lungs, rather than with traditional measures of viral titer and host responses. Strain-specific differences included hypercytokinemia in H5N1 infections that was not seen with the H7N9 infections regardless of lethality. Conversely, H7N9 viruses showed a greater tropism for respiratory epithelium covering nasal passages and NALT than H5N1 viruses, which may explain the enhanced transmission in ferret models. Overall these studies highlight some distinctive properties of H5N1 and H7N9 viruses in different in vitro and in vivo models.