Background: Neuromyelitis optica (NMO) is an uncommon neuro- inflammatory syndrome that has shown to be distinct from multiple sclerosis (MS) and associated with the autoantibody marker NMO-immunoglobulin G (IgG). There are still only a few studies regarding the epidemiology of NMO in Iran. In the present study, we tried to describe the epidemiology of NMO in Khuzestan as one of the densely populated regions in Iran.Methods: A cross-sectional study was performed during the period 2013-2014. Multiple regional sources of data were used including hospital records, details from neurologists and MS society database. The diagnosis of NMO was based on clinical presentation, abnormal findings on neuroimaging and serological tests.Results: A 51 Caucasian patients (36 patients with NMO and 15 with NMO-spectrum disorder) were identiﬁed with a female/male ratio of 7.5:1.0. The crude prevalence of NMO was 1.1/100,000 population. The mean age at onset was 29.2 ± 6.1 years and the mean duration of symptoms was 5.0 ± 0.4 years. The majority of patients (60.8%) were classified as having mild disability (Expanded Disability Status Scale = 0-3.5). Among of 35 patients whose titer of NMO-IgG was measured, 19 (54.2%) were seropositive.Conclusion: Our study suggests that NMO prevalence rate in South West Iran (Khuzestan Province) is much lower than that reported for MS prevalence rate (16.2/100,000) and our patients had a lower age at onset presentation and milder course of the disease than western countries.