Multiple sclerosis (MS) in Asian populations is often characterized by the selective involvement of the optic nerve (ON) and spinal cord (SP) (OSMS) in contrast to classic MS (CMS), where frequent lesions are observed in the cerebrum, cerebellum, or brainstem, as well as in the ON and SP. In Western countries, inflammatory demyelinating disease preferentially involves the ON and SP is called neuromyelitis optica (NMO). Recently, Lennon et al. have reported that NMO-immunoglobulin G (NMO-IgG), which has been shown to bind to aquaporin 4 (AQP4), could be a specific marker of the NMO. To examine the epidemiological and clinical spectra of Japanese MS with this antibody, we established an immunohistochemical detection system for the AQP4-Ab using the AQP4-transfected human embryonic kidney cell line (HEK-293) and confirmed AQP4-Ab positivity together with the immunohistochemical staining pattern of NMO-IgG in approximately 60% of Japanese MS patients with long spinal cord lesions extending over three vertebral segments (LCL (+) MS). Patients with OSMS without LCL and those with classic MS were negative for this antibody. AQP4 is totally lost in the OSMS lesions. The AQP4-Ab titer correlates with the activity of the disease and the symptom improves after plasma exchange. These results suggested the close relation to the pathogenesis of AQP4-Ab to NMO/OSMS.