Multiple sclerosis (MS) is a chronic immune-mediated central nervous system (CNS) disorder with several environmental and genetic factors. To participate in the regulation of immune responses, long non-coding RNAs (lncRNAs) have recently been published. As a result, aberrant expression of lncRNAs has been proposed as an underlying cause of MS. In the current research, by means of quantitative real-time polymerase chain reaction (PCR), we assessed the expression levels of two lncRNAs with putative functions in the regulation of immune response, namely lncRNA-H19 and lincRNA-p21, in serum of 74 Egyptian patients with MS relative to healthy people. Significant downregulation of lncRNA-H19 and lincRNA-P21 expression levels relative to controls in the serum of MS patients was observed (P < 0.001). Correlation analyses of lncRNA expression levels and MS patient clinical data showed a substantial moderate positive linkage among lincRNA-p21 serum expression levels and the Expanded Disability Status Scale (EDSS), a substantial moderate negative linkage among lncRNA-H19 expression levels and MS onset age and no substantial correlation among these lncRNAs and patient age. Furthermore, we showed no significant correlation among lncRNA-H19 and lincRNA-p21 serum expression levels. In brief, in MS patients, we have shown dysregulation of two lncRNAs. To explore the precise mechanisms through which lncRNAs engage in the regulation of immune responses, more studies are required.