Background <p>Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are autoimmune demyelinating diseases with overlapping clinical features but distinct patterns of brain and spinal cord atrophy. The precise atrophy subtypes specific to each disease remain elusive. This study aimed to identify shared and distinct atrophy subtypes in NMOSD and MS, using neuroimaging to explore their clinical significance and potential implications for tailored treatment strategies.</p> Methods <p>Clinical and MRI data of 278 AQP4 + NMOSD and 391 MS patients were retrospectively and prospectively collected, alongside 1,065 healthy controls. 3D T1-weighted image derived structural measurements were used in a Subtype and Stage Inference model, to identify distinct brain and spinal cord atrophy subtypes of NMOSD and MS. The clinical characteristics of disease atrophy subtypes and clinical associations of atrophy stage were investigated.</p> Results <p>The results showed that in NMOSD, three atrophy subtypes were identified: (1) cortical subtype with severe cognitive and physical disability; (2) spinal cord subtype with high number of relapses; and (3) cerebellum subtype with a favorable prognosis. In MS, three atrophy subtypes were identified: (1) cortical subtype featuring severe cognitive decline; (2) spinal cord subtype featuring high number of relapses; and (3) subcortical subtype featuring severe physical disability. Advanced stages in MS spinal cord and subcortical atrophy subtypes were associated with severe physical disability and cognitive decline, while advanced stage in all MS subtypes correlated with disability worsening.</p> Conclusions <p>These novel imaging subtypes in NMOSD and MS may help interpret disease heterogeneity, develop stratified management, and assess prognosis.</p>