OBJECTIVE : Antibodies to myelin oligodendrocyte glycoprotein (MOG-ab) and antibodies to aquaporin-4 (AQP4-ab) have been suggested to play roles in commonly separated subsets of patients with neuromyelitis optica spectrum disorder (NMOSD) phenotypes. The aim of this study is to quantitatively delineate and compare the brain lesion distributions of AQP4-ab-positive and MOG-ab-positive patients. METHODS : Fifty-seven and twenty-eight clinical MRI scans were collected from fifty-two AQP4-ab-positive and twenty-four MOG-ab-positive patients, respectively. T2 lesions were segmented manually on each axial FLAIR image. Probabilistic lesion distribution maps were created for each group after spatial normalization. Lobe-wise and voxel-wise quantitative comparisons of the two distributions were performed. A classification model based on the lesion distribution features was constructed to differentiate the two patient groups. RESULTS : Infratentorial and supratentorial brain lesions were found in both AQP4-ab-positive and MOG-ab-positive patients, with large inter-group overlap mainly in deep white matter (WM). In comparison with those in the AQP4 group, the brain lesions of the MOG-ab-positive patients had a larger size, dispersed distribution, and higher probabilities in the cerebellum, pons, midbrain, and GM and juxtacortical WM in temporal, sublobar, frontal, and parietal lobes. The area under the receiver operating characteristic curve of the lesion-distribution-based classification model was 0.951. CONCLUSIONS : MOG-ab-positive and AQP4-ab-positive groups showed similar but quantitatively different brain lesion distributions. These results may help clinicians in considering MOG versus AQP4 in initial diagnosis, and add rationale for sending corresponding serologic testing. CONCLUSIONS : • Brain lesion distributions of AQP-ab-positive and MOG-ab-positive NMOSD patients • Larger size, dispersed distribution, higher lesion probabilities in the cerebellum, pons, midbrain, and GM and juxtacortical WM in the MOG group • The lesion-distribution-based classification model differentiates the two groups with AUC = 0.951.