Background and Objective: Neuromyelitis optica (NMO) shares certain features with multiple sclerosis (MS). Similar phenotypes, wide spectrum and the differential prevalence of NMO among ethnic backgrounds pose diagnostic challenges. NMO-IgG antibodies are specific biomarker for NMO and facilitate its differentiation from other demyelinating diseases. This study aimed to assess the frequency of NMO and NMO-IgG seropositivity in Saudi patients with demyelinating diseases of the central nervous system. Methods: One hundred and four patients from neurology database at King Abdulaziz Medical City, Riyadh underwent clinical and laboratory examination, neuroimaging and NMO-IgG antibodies screening. Results: The mean age at presentation was 32 (±9) years and there was an excess of females (female:male – 3:1). The mean duration of illness was 4.6 (±3.2) years. During the illness, 48.1% of patients had clinical evidence of spinal cord involvement, 29.8% had optic neuritis and 14.4% had both features. A large majority (75.8%) of brain lesions fulfilled MRI criteria for MS and 17% had lesions extending over ≥3 vertebral segments. NMO-IgG antibodies were present in only one patient – a frequency of 0.96% in our study cohort. Conclusion: Prevalence of NMO and NMO-IgG seropositivity is rare in Saudis with demyelinating diseases of the central nervous system. Hence, routine NMO-IgG testing is likely to have a low diagnostic yield