Background: Multiple sclerosis is a central nervous system autoimmune illness that is characterized by chronic inflammation, gliosis, demyelination, and neuronal loss. Long noncoding RNAs (LncRNAs) play a significant role in regulating immune response, as well as the development of immune cells. Objective: This study aims investigate the role of lncRNAs; HOTAIR (HOX transcript antisense intergenic RNA) and (HOX transcript antisense intergenic RNA) in MS pathophysiology and their impact on clinical course of the disease. Patients and methods: The present study was conducted on 134 subjects; 74 patients with MS (relapsing remitting and secondary progressive types) and 60 age and sex matched controls. Expression of both lncRNAs; HOTAIR and GAS-5 was assessed in serum using Real-time quantitative PCR (qPCR). The clinical disability in the patients was evaluated using the Expanded Disability Status Scale (EDSS) at the time of patient enrollment. Results: The relative expression levels of HOTAIR were significantly down-regulated in serum samples of MS patients relative to the control group; (p value < 0.001) while relative expression levels of GAS-5 were significantly up-regulated in serum samples of MS patients relative to the control group; (p value = 0.002). There is significant positive association between GAS-5 expression level and age of onset in MS patients (P value= 0.020). Conclusion: This differential expression of both lncRNAs may have an important role in MS pathophysiology. This study clarified the molecular pathways through which those lncRNAs contribute to MS clinical presentation.