Central nervous system lesions of chickens inoculated with three highly pathogenic avian influenza virus strains, A/chicken/Victoria/1/85 (H7N7), A/turkey/England/50-92/91 (H5N1), and A/tern/South Africa/61 (H5N3), were examined histologically and immunohistochemically. The chickens either died within 7 days of inoculation or were killed 2 weeks after inoculation. No significant differences were observed in the lesions induced by these three viruses. The lesions were divided into two types, disseminated foci of microgliosis and necrosis, and ventriculitis. The former lesions were associated with infection of the vascular endothelium and dissemination of the virus to the peripheral parenchymal cells of the chickens that died within 3 days of inoculation. The ventriculitis lesions, however, were observed mainly in the chickens that died between 4 and 7 days after inoculation. These findings suggest that viral infection of the vascular endothelium and subsequent involvement of ependymal cells play important roles in the pathogenesis of the central nervous system lesions.