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Most patients with neuromyelitis optica (NMO) and many with NMO spectrum disorder have autoantibodies against aquaporin-4 (AQP4-Abs), but recently, myelin-oligodendrocyte glycoprotein antibodies (MOG-Abs) have been found in some patients. Here, we showed that patients with NMO/NMOSD with MOG-Abs demonstrate differences when compared with patients with AQP4-Abs.To characterize the features of patients with NMO/NMOSD with MOG-Abs and compare them with patients with AQP4-Ab–positive NMO/NMOSD.This observational study was conducted at a single UK specialist center for NMO. Patients with a first demyelinating event between January 1, 2010, and April 1, 2013, seen within the Oxford NMO service and who tested positive for MOG-Abs or AQP4-Abs were included in the study.Cell-based assays using C-terminal–truncated human MOG and full-length M23-AQP4 were used to test patient serum samples for AQP4-Abs and MOG-Abs.Demographic, clinical, and disability data, and magnetic resonance imaging findings.Twenty AQP4-Ab–positive patients and 9 MOG-Ab–positive patients were identified. Most patients in both groups were white. Ninety percent of AQP4-Ab–positive patients but only 44% MOG-Ab–positive patients were females (P = .02) with a trend toward older age at disease onset in AQP4-Ab–positive patients (44.9 vs 32.3 years; P = .05). MOG-Ab–positive patients more frequently presented with simultaneous/sequential optic neuritis and myelitis (44% vs 0%; P = .005). Onset episode severity did not differ between the 2 groups, but patients with MOG-Abs had better outcomes from the onset episode, with better recovery Expanded Disability Status Scale scores and a lower risk for visual and motor disability. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging (75% vs 17%; P = .02) and involvement of deep gray nuclei on brain magnetic resonance imaging (P = .03). Cerebrospinal fluid characteristics were similar in the 2 groups. A higher proportion of AQP4-Ab–positive patients relapsed (40% vs 0%; P = .03) despite similar follow-up durations.Despite the fact that patients with MOG-Abs can fulfill the diagnostic criteria for NMO, there are differences when compared with those with AQP4-Abs. These include a higher proportion of males, younger age, and greater likelihood of involvement of the conus and deep gray matter structures on imaging. Additionally, patients with MOG-Abs had more favorable outcomes. Patients with AQP4-Ab–negative NMO/NMOSD should be tested for MOG-Abs.