Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system, and humoral immunity is suggested to play an important role in the pathogenesis. The identification of an anti-aquaporin-4 antibody (AQP4-Ab, neuromyelitis optica immunoglobulin G) in the sera of patients with NMO has led to the investigation on the pathogenicity of the autoantibody. Recent immunohistological analyses revealed the primary loss of AQP4 on astrocytes and complement deposition in active lesions of NMO. In this report, we show that astrocytes are susceptible to sera from AQP4-Ab-positive patients and undergo necrosis in a complement-dependent manner. Our results suggest the primary pathogenic role of AQP4-Ab in NMO.