BACKGROUND Recent studies have shown that tissue damage in neuromyelitis optica (NMO) is not limited to the spinal cord and optic nerve but can also appear in the brain. Previous magnetic resonance imaging (MRI) studies have reported controversial findings regarding the presence of white matter atrophy in NMO patients. OBJECTIVE To investigate regional white matter changes in NMO using voxel-based morphometry (VBM). METHODS Conventional MRI and T1-weighted three-dimensional MRI were performed on 20 patients with NMO and 20 age- and sex-matched normal controls (NCs). The data were analyzed by statistical parametric mapping 5 (SPM5) to generate white matter concentration maps, and regional white matter concentrations were compared between the two groups. Relationships between the white matter concentration in regions with significant group differences and the Expanded Disability Status Scale (EDSS) and disease duration were further explored. RESULTS Compared to NCs, NMO patients had decreased white matter volumes in the right precentral gyrus, right postcentral gyrus, left middle and medial frontal gyrus, right superior frontal gyrus, bilateral inferior and superior parietal lobule, right angular gyrus, right middle occipital gyrus, and left precuneus. No significant correlation was found between white matter regions with volume reduction and the EDSS and disease duration in NMO. CONCLUSIONS We found white matter atrophy in several brain regions in the frontal, parietal, and occipital lobes in NMO, suggesting that subtle white matter damage relevant to the motor, vision, and cognition systems exists in NMO patients. The pattern of white matter atrophy in NMO is different from that in multiple sclerosis (MS).