Objectives Multiple sclerosis is an inflammatory condition of the central nervous system whose etiology is influenced by immunologic, genetic, and environmental factors. Aim of the present study was to determine if any relation exists between IL-18 -137C/G and -607C/A gene promoter polymorphisms on the individual susceptibility of multiple sclerosis and also to investigate the possible effect of IL-18 activity regarding this kind of polymorphism and MS. Patients and methods 113 patients with clinically definite MS and 135 ethnically-matched controls were participated in this study. IL-18 -137C/G and -607C/A gene promoter polymorphisms were analyzed by Sequence Specific Polymerase Chain Reaction (SS-PCR), while levels of serum IL-18 were measured by Enzyme Linked Immunoassay Assay (ELISA) in patients with MS and healthy controls. Results Our results showed that the IL-18 -607AA genotype indicated 6 times higher risk in the development of MS (OR = 6.883; 3.17-14.96; p < 0.001). According to our findings, smoking seems to be an important confounding factor in MS patients with carrying IL-18 -607 AA and CA + AA genotypes. However, no meaningful association was found with IL-18 -137C/G gene promoter polymorphism. Conclusion In conclusion, we suggest that IL-18 -607C/A gene promoter polymorphism is a major genetic factor for determining individual susceptibility to MS, where smoking status also increases the risk of MS.