Introduction: To protect genomes of all organisms from internal and external damages and maintain the genome integrity and the continuity of life, repair system has been developed in all living cells. Defects in repair system are responsible for various kinds of disease including cancers and neurodegenerative diseases such as Multiple sclerosis (MS). The relationship between various components of the repair system and MS has been confirmed by investigations on separate cohorts in independent research. The main aim of this study was to discover the genetic association of two functional polymorphisms of rs1799782 in XRCC1 and rs2303425 in MSH2 genes as the key players in DNA repair system; with MS. Methods: The genotypes of 105 MS patients and 102 age and sex matched healthy controls for these polymorphisms were determined by a PCR-RFLP technique. Results: Genotype and allele frequencies of rs1799782 in patients with MS compared to the control group demonstrated a significant difference and a possible role for this polymorphism in MS pathogenesis (P value (0.02) and OR (3.4)). The rs2303425 polymorphism showed no significant correlation (P value = 0.41 and OR=1.5) with the risk of MS in Iranian population. Conclusion: Our results suggest a possible role for repair system genes and their significance in the pathogenesis of multiple sclerosis.