Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are a rare neuroinflammatory disease. Compared to multiple sclerosis, brain lesions are less frequent, although may contribute to patient disability. Using clinical, demographic, and magnetic resonance imaging (MRI) data collected in the PArallel MRI in NmOsd (PAMRINO) study, we performed an initial phenotyping using principal component analysis (PCA). Objectives: Evaluate patient phenotypic groups from PCA applied to quality-checked clinical, demographic, and MRI cross-sectional data collected from an international aquaporin-4 antibody (AQP4-ab) seropositive NMOSD cohort. Aims: Investigate PCA components for patient phenotypes and their relationship with disability, as measured by the expanded disability status scale (EDSS). Methods: Data were acquired from 17 international centres, where 177 AQP4-ab seropositive NMOSD patients were included based on matching clinical and MRI visit data. Data input in the PCA were clinical (time since onset, EDSS, optic neuritis, transverse myelitis, acute brainstem, acute area postrema (AP) attacks), demographic (age, age at onset, sex, centre, ethnicity), and brain MRI radiological (18 lesion categories: whole brain, central vein sign (CVS), U-fiber, cortical, juxtacortical, corpus callosum, multifocal, third ventricle, lateral ventricle (LV), cerebellar, vascular, brainstem, AP, mesencephalon, other circumventricular organs (OCO), fourth ventricle, pons, medulla oblongata (MO)) findings. Unsupervised 3-component PCA was performed to categorise patients into phenotypic groups. Principal components were then further analysed for differences in disability, based on the EDSS, using a Wilcoxon rank sum test. Results: The 3 PCA components had similar median EDSS. Component 1 (C1) and C2 showed statistically different EDSS (W=1065.5, p=0.017). Patients in C2 had higher EDSS (range: 1.5-9.5), with top 5 phenotypic contributions from: presence of AP, MO, and brainstem lesions in ⩾37% of patients, with 100% absence of CVS and lesions in OCO. C1 patients had lower EDSS (range: 0-9), where ⩾57% of patients had multifocal, LV and/or juxtacortical lesions, combined with few (less than 12% of patients) fourth ventricle and/or mesencephalon lesions. Conclusions: Presence of AP, brainstem, and MO lesions without CVS or OCO lesions are a phenotypic group of NMOSD patients with higher EDSS. Unsupervised PCA may aid in defining red-flags for higher disability, based on MRI findings.