Chickens and domestic ducks were inoculated with highly pathogenic avian infiuenza viruses (H5N1) isolated in Japan in 2007 and 2008. The virus strain A/chicken/Miyazaki/K11/2007 caused 100% mortality in chickens with characteristic skin lesions on the head that were similar to those found in field chicken outbreaks in 2007. The virus strain A/whooper swan/Akita/1/2008 (Ws/Akita/1/08) isolated from dead wild swans was also highly pathogenic against chickens. When domestic ducks were inoculated with each virus, only Ws/Akita/1/08 caused mortality. Two characteristic clinical signs, a neurologic sign and corneal opacity, were observed in domestic ducks. Histologically, edematous and hemorrhagic skin lesions at the comb and wattle were the most prominent findings in dead chickens. In domestic ducks, non-suppurative meningoencephalitis, myocarditis, pancreatic focal necrosis, keratitis, and epidermal necrosis of the feathers and beak were observed, depending on the course of infection. Immunohistochemical testing revealed that, compared to chickens in which the virus preferably replicated in systemic endothelial cells, antigen distribution in domestic ducks was confined to the parenchymal cells of some organs such as the brain, heart, pancreas, and epidermis of the feathers and beak. Our data suggest that, in addition to the increased mortality rate, skin lesions of the head including the wattle and comb comprise an important clinical sign in chickens for detection of highly pathogenic avian infiuenza viruses (H5N1) isolated in Japan. On the other hand, the neurologic signs and corneal opacity can be useful indications for detecting infected waterfowl.