The objective is to assess the frequency of AQP4-Ab in Chinese patients with optic neuritis (ON) and to investigate the prognostic implications of AQP4-Ab seropositivity in such patients. The presence of aquaporin-4 (AQP4) antibodies in human AQP4-transfected cells was determined by indirect immunofluorescence, and the diagnostic and prognostic relevance of AQP4 antibodies in 215 Chinese patients with optic neuritis was evaluated. The patients were enrolled from the Chinese People's Liberation Army General Hospital (PLAGH) and followed up to 1-228 months. Kaplan-Meier survival analysis was used to investigate the visual outcomes and prognostic characteristics of 70 patients who were aquaporin-4 antibody seropositive, and altogether 115 eyes were involved. AQP4-Ab was detectable in 70/215 (32.6%) patients with acute monosymptomatic optic neuritis. These AQP4-Ab seropositive patients were diagnosed as sufferers of neuromyelitis optica (NMO) (n = 10), NMO spectrum disease (NMOSD) (n = 41), multiple sclerosis (MS) (n = 1), and acute optic neuritis (AON) (n = 18). Moreover, AQP4-Ab levels did not vary between seropositive AON and NMO-ON and did not correlate with disease severity. Finally, the male gender, older age at onset, number of relapses, concomitant autoimmune antibodies, and optic lesions in magnetic resonance imaging (MRI) were associated with the AQP4-Ab seropositive status and the risk of developing permanent visual disability. Acute optic neuritis has a higher incidence of anti-aquaporin-4 antibody in China than in Western countries, and AQP4 antibody is a sensitive and specific biomarker for discriminating NMO-ON from other types of optic neuritis during the early stage of the disease course.