In this experimental model of EAE in C57/BL6 mice in which passively transferred IgG from NMO patients is infused at onset of neurologic disease, we conclude that the anti-AQP4 antibody contributes to the pathogenicity by targeting subpial astrocytes leading to large, confluent demyelinated lesions in the spinal cord and optic nerve. Here, AQP4 is linked to neuromyelitis optica.