To investigate whether AQP4 autoantibodies (AQP4-Ab) are causative for neuromyelitis optica (NMO), the production of AQP4-Ab and clinical experimental autoimmune encephalomyelitis (EAE) was investigated in mice administered with mouse AQP4 antigen or myelin oligodendrocyte glycoprotein (MOG(35-55)) alone, and in combination. Eight- to twelve-week-old female C57BL/6 mice were randomly immunized with encephalitogenic mixture containing 300 mu g of MOG(35-55) or AQP4 antigen alone, and in combination in complete Freund's adjuvant supplemented with H37Ra M. tuberculosis. The incidence of EAE, Weaver 15 scores, and body weight was evaluated. ELISA was used to detect serum mouse AQP4-Ab. Mice injected with MOG(35-55) and MOG(33-55) plus AQP4 antigen began to show EAE symptoms 12 days after immunization. The incidence of EAE was 91.6%, and 62.5%, for MOG(35-55) alone and MOG(33-55) plus AQP4 antigen groups, respectively, while AQP4 antigen alone didn't develop EAE. In all but the control group, serum AQP4-Ab levels were increased, and correlated positively with Weaver 15 score (r(s) = 0.713, p = 0.000) and negatively with body weight changes (r(s) = -0.415, p = 0.011). Injection of human NMO sera positive for AQP4-Ab exacerbated MOG-induced EAE. Our results suggest that AQP4-Ab can be produced in MUG-induced MS model, and itself is not sufficient for the development of EAE, implying that NMO might be a subtype or transition from MS. Published by Elsevier B.V.