During the 2003 to 2004 outbreak of avian influenza A (H5N1) virus in Asia, there were anecdotal reports of fatal infection in domestic cats, although this species is considered resistant to influenza. We experimentally inoculated cats with H5N1 virus intratracheally and by feeding them virus-infected chickens. The cats excreted virus, developed severe diffuse alveolar damage, and transmitted virus to sentinel cats. These results show that domestic cats are at risk of disease or death from H5N1 virus, can be infected by horizontal transmission, and may play a role in the epidemiology of this virus.