We retrospectively analyzed and compared patterns of anti-aquaporin-4 (AQP4) immunoreactivity of autopsied brains of 2 patients with classical multiple sclerosis (MS) and 2 patients with neuromyelitis optica (NMO). Serological examination for NMO-IgG was not performed in all the cases. We confirmed that the expression of AQP4 is strongly inhibited in demyelinating lesions of NMO, accompanied by the loss of grial fibrillary acidic protein (GFAP) expression. The expression of AQP4 is preserved in MS lesions losing myelin basic protein (MBP) positivity. Therefore, AQP4 immunoreactivity may distinguish NMO from MS neuropathologically. NMO preferentially exhibited central lesions of the spinal cord with strongly necrotizing features and axonal injury. One NMO patient with oligoclonal band in the cerebrospinal fluid presented severe necrotizing lesions of the corpus callosum, cerebral white matter in addition to optic nerves and longitudinally extensive spinal cord lesions. Another patient with MS presented longitudinally extensive spinal cord lesions and a lesion in the medullary tegmentum in the floor of the fourth ventricle, which is reported to be one of the vulnerable lesions of NMO. We also reported a patient with NMO accompanied with Sj?gren syndrome. These findings suggest that longitudinally extensive spinal cord lesions and medullary tegmentum lesion may be found in MS,and cerebral white matter lesion may be found in NMO. The distribution of lesions may overlap in MS and NMO although the immunoreactivity of AQP4 differs in these 2 conditions.