Multiple Sclerosis (MS) is a complex chronic neurodegenerative disorder resulting from an autoimmune reaction against myelin. So far, many genetic variants have been reported to associate with MS risk however their association is inconsistent across different populations. Here we investigated the association of the most consistently reported genetic MS risk variants in the Kuwaiti MS population in a case-control study designs. Of the 94 reported MS risk variants four variants showed MS risk association in Arabs exome analysis (EVI5 rs11808092 p = 0.0002; TNFRSF1A rs1800693 p = 0.00003; MTHFR rs1801131 p = 0.038; and CD58 rs1414273 p = 0.00007). Replication analysis in Kuwaiti MS cases and healthy controls confirmed EVI5 rs11808092A (OR: 1.6, 95%CI: 1.19-2.16, p = 0.002) and MTHFR rs1801131G (OR: 1.79, 95%CI: 1.3-2.36, p = 0.001) as MS risk genetic factors, while TNFRSF1A rs1800693C had a marginal MS risk association (OR: 1.36, 95%CI: 1.04-1.78, p = 0.025) in the Kuwaiti population. CD58 rs1414273 did not sustain risk association (p = 0.37). In conclusion, EVI5 rs11808092A, TNFRSF1A rs1800693C and MTHFR rs1801131G are MS risk factors in the Kuwaiti population. Further investigations into their roles in MS pathogenesis and progression are merited.