Background: It remains uncertain whether neuromyelitis optica (NMO) exhibits diffuse cerebral abnormalities or whether the pathology is truly restricted to optic nerves and spinal cord in the majority of cases. We examined NMO patients with diffusion tensor imaging (DTI) and utilized a tract-based spatial statistics (TBSS) method to analyze the data. Methods: Twenty-seven NMO patients (25 females, age mean +/- SD: 35.1 +/- 12 years) and 27 age-and sex-matched normal controls were included in this study. Voxel-wise analyses were performed with TBSS using multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(1)) and radial diffusivity (lambda(23)). Results: The NMO patients had significantly increased MD (3.6%), lambda(1) (2.6%) and lambda(23) (4.6%) in their white matter (WM) skeletons compared with the controls. Furthermore, TBSS analyses revealed significantly (p < 0.05, corrected for multiple comparisons) increased diffusivities (MD, lambda(1) and lambda(23)) in many cerebral WM tracts in the patients with NMO, including the superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, corpus callosum, cingulum bundles, corticospinal tracts, optic radiation, uncinate fasciculi, fornices, internal capsules, external capsules and cerebral peduncles. Exploratory analyses also revealed the possible associations between WM diffusion changes (MD, lambda(1) and lambda(23)) and clinical variables (Expanded Disability Status Scale and disease duration) in the patients. Conclusions: This study provided imaging evidence for widespread cerebral WM abnormalities. While these findings require independent replication, they potentially signify the presence of widespread, low-grade cerebral pathology in NMO.