This study aimed to investigate the alterations of brain volumetry and associated structural covariance in subcortical regions in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD).Fourty MS patients, 35 NMOSD patients and 34 healthy controls (HC) underwent 3D T1-weighted image and 3D T2 FLAIR of MRI. The volume differences in subcortical regions were compared between the MS, NMOSD, and HC groups by automated brain volumetry. Structural covariance analysis was performed with each pair of these regions to investigate the alterations of anatomical connections in MS and NMOSD compared to HC.Compared with HC, MS patients presented significantly smaller volume in some subcortical and infratentorial regions (P<0.05), while NMOSD patients showed no significant difference of volumetry in any of the brain regions (P>0.05), although they had no significant difference in disease duration (MS 3.95±3.73 ys; NMOSD 3.11±4.61 ys; P>0.05). In addition, the structural covariance analyses revealed synergic volume alteration in subcortical regions both in the MS and NMOSD groups. More extensive additional connections compared with HC were found in MS patients and more extensive missing connections compared with HC were found in NMOSD patients.This study revealed distinct patterns of brain structural damage and reorganization in MS and NMOSD, which could facilitate a better distinction between these two entities.Copyright © 2023 Elsevier B.V. All rights reserved.