In India, Neuromyelitis optica spectrum disorders (NMOSD) can often be misdiagnosed as multiple sclerosis (MS) leading to wrong or delayed treatment. Although diagnostic criteria exist it is important to flag certain highlights in the phenotype by direct comparison which will prompt investigation in the right direction. The aim was to identify distinguishing features, especially differences in disability status and frequency of the optico-spinal syndrome. This study was designed as a multicentric, hospital based, ambispective, observational study of patients with primary demyelination due to either NMOSD or MS. Various variables were collected using a data extraction proforma and were compared using statistical means. A total of 212 patients, 166 (78.3%) with MS and 46 (21.7%) with NMOSD, were included from six different cities across India. The male to female ratio was 1:1.3 in MS group and 1:2.3 in NMOSD group. Significant differences on logistic regression included: patients with NMOSD were more disabled despite having a shorter duration of illness with a high progression index (EDSS/ duration of disease in years) of 5.99 vs 0.74 respectively (p = 0.02); in subset of relapsing patients relapsing optico-spinal syndrome (optic neuritis with myelitis) was more common in NMOSD (39.1% vs 0.8%); presence of at least one T2 lesion in the last available MRI brain (78.6% vs 39.1%) and presence of at least one gadolinium enhancing lesion in brain MRI documented during course of illness (30.2% vs 8.7%) was more in MS patients. If the patient with demyelination had a progression index of ≥ 0.39, the Likelihood Ratio (LR) of having NMOSD was 1.32 (95% CI 1.06-1.64), the sensitivity was 0.74 and specificity 0.44. Other notable variables significant on univariate but not on multivariate analysis were: other autoimmune diseases were present more in the NMOSD group (13% vs 2.4%); proportion of patients who had only school education (up to class 12) but not higher were more in NMOSD (67.4% vs 38.5%); the most common clinical presentation in MS patients was either a brainstem or cerebral syndrome (41% vs 21.8%) while it was isolated myelitis in NMOSD patients (37% vs 19.3%). Other findings included: optic neuritis as a presenting feature was common and present in similar proportions in both the groups (around 37%); 50% (23/46) of NMOSD and around 30% (50/166) of MS patients had a single clinical episode during the course of their illness and in the relapsing patients, mean no of relapses (around 2.7) and ARR (MS 0.38, NMOSD 0.54) were similar. Secondary progressive MS was diagnosed in 4.8% (8/166) and primary progressive MS was diagnosed in 3.7% (6/166). Index of suspicion for NMOSD should be high in a patient if: the course is relatively short; disability is out of proportion and progression index is ≥0.39 or the patient has had recurrent optico-spinal relapses. It is important to distinguish early in the course NMOSD from MS as timely specific treatment may prevent future disability. Copyright © 2020 Elsevier B.V. All rights reserved.