Highly pathogenic avian influenza viruses (HPAIV) of the H5 and H7 subtypes primarily infect poultry but are occasionally transmitted to humans and other mammalian species, often causing severe disease. Previously we have shown that HPAIV H5N1 causes severe systemic disease in cats. In this study, we investigated whether HPAIV H7N7 isolated from a fatal human case is also able to cause disease in cats. Additionally, we compared the cell tropism of both viruses by immunohistochemistry and virus histochemistry. Three domestic cats were inoculated intratracheally with HPAIV H7N7. Virus excretion was restricted to the pharynx. At necropsy, 7 days post inoculation, lesions were restricted to the respiratory tract in all cats. Lesions consisted of diffuse alveolar damage and colocalized with virus antigen expression in type II pneumocytes and nonciliated bronchiolar cells. The attachment patterns of HPAIV H7N7 and H5N1 were similar: both viruses attached to nonciliated bronchiolar epithelial cells, type II pneumocytes, as well as alveolar macrophages. These data show for the first time that a non-H5 HPAIV is able to infect and cause respiratory disease in cats. The failure of HPAIV H7N7 to spread beyond the respiratory tract was not explained by differences in cell tropism compared to HPAIV H5N1. These findings suggest that HPAIV H5N1 possesses other characteristics that allow it to cause systemic disease in both humans and cats.