Five dogs 2 to 8 years old with old dog encephalitis were compared to five other dogs, 4 to 8 1/2 years old, with prolonged multifocal demyelinating distemper encephalitis. The dogs with old dog encephalitis had a diffuse panencephalitis involving most areas of the central nervous system with relative sparing of the cerebellum. The clinical signs were related to the cortical and subcortical lesions. The other dogs had severe focal necrotizing lesions mostly in the cerebellum and in the vicinity of the fourth ventricle; clinical signs were related to brainstem and spinal cord lesions. Viral isolation attempts were unsuccessful in the dogs with old dog encephalitis. In two dogs with multifocal encephalitis, canine distemper virus was isolated in tissue culture. The differences in lesions, clinical signs and observations in vitro indicate differences in pathogenesis between old dog encephalitis and multifocal demyelinating distemper encephalitis although both diseases may be caused by the same agent.