Pathologic findings in mature dogs with old dog encephalitis were compared with the findings in multiple sclerosis, subacute sclerosing panencephalitis and neuromyelitis optica in man. Fluorescent antibody studies in animal and human tissues were compared. Optic neuritis in dogs with chronic distemper shows changes similar to those in the optic tract of human patients with severe demyelinating disease. The pathologic changes in multiple sclerosis, such as perivascular infiltration with lymphocytes, plasma cells and demyelination are similar to those seen in old dog encephalitis. Demyelination in old dog encephalitis is usually diffuse. The findings strongly support a possible relationship of old dog encephalitis to multiple sclerosis, subacute sclerosing panencephalitis, and neuromyelitis optica.