Neuromyelitis optica (NMO) and multiple sclerosis (MS) are two of the autoimmune inflammatory demyelinating diseases in the central nervous system. Complement is thought to have an important role in pathogenesis of these diseases, especially in NMO. However, the change of terminal complement complex (TCC, C5b-9) in patients with NMO is still unclear. Cerebrospinal fluid (CSF) C3a, C5a, sC5b-9 were measured by enzyme-linked immunosorbent assay in patients with NMO (n = 26), MS (n = 25) and other neurological disease (OND, n = 19). CSF levels of C5a in patients with NMO were higher than patients with OND (P = 0.006). Increased CSF sC5b-9 were found in the patients with NMO compared with patients with MS (P = 0.029) and OND (P = 0.0001). CSF sC5b-9 in patients with MS were also higher than patients with OND (P = 0.030). Patients with NMO revealed a trend to an increased disease disability with increased CSF sC5b-9 during relapse but not in MS (NMO: P = 0.006, MS: P = 0.097). CSF levels of sC5b-9 are increased in patients with NMO and reflect the activation of complement in NMO.