OBJECTIVE To investigate the relationship between neuromyelitis optica spectrum disorder (NMOSD) and autoantibodies. METHODS Blood samples of 108 NMOSD patients and 38 controls were collected from January 2012 to August 2014. Immunological parameters, including anti-aquaporin 4, antinuclear, anti-ribonucleoprotein, anti-SM, anti-SSA/Ro, anti-SSB/La and anti-ribosomal P-protein autoantibodies were examined. RESULTS The NMOSD group exhibited a significantly higher percentage of anti-aquaporin 4 antibodies compared with the control group (76.9 vs. 0.0%, p = 0). The positive rates for antinuclear and anti-SSA antibodies in the NMOSD group were also higher than in the control group (35.2 vs. 11.8%, p = 0.001; 13.0 vs. 0.0%, p = 0.044). In total, 36.1% of the patients in the NMOSD group were seropositive for autoantibodies but only 8.3% were diagnosed with definite systemic autoimmune disorders. CONCLUSIONS NMOSD is closely associated with elevated autoantibodies, particularly antinuclear and anti-SSA/Ro antibodies. NMOSD rarely coexists with organ-specific autoimmune diseases.