IL-8 plays important roles in CNS development, modulation of neuronal survival and excitability. Among IL-8 receptors, only CXCR2 is known to be present in the brain. The ability of individuals in producing IL-8 is partially determined by IL-8 -251 A/T polymorphism. Therefore, the aim of the present study was to investigate the association between IL-8 -251 A/T and CXCR2 +1208 C/T gene polymorphisms and susceptibility to multiple sclerosis (MS). Two hundred and twenty-three MS patients and 319 healthy and ethnic matched controls were included in this study. IL-8 promoter (-251 A/T) and CXCR2 (+1208 C/T) gene polymorphisms were genotyped via allele specific PCR (AS-PCR) method. A significant difference was found in IL-8 -251 A/T polymorphism between MS patients and controls (p = 0.04). This deference was a result of a higher incidence of the low producer allele of IL-8 (T allele) in MS patients compared to controls. However, there was no significant association between different clinical findings (EDSS score, progression index, disease onset age, and the type of disease) and IL-8 -251 A/T polymorphism. Furthermore, no significant association existed between CXCR2 +1208 C/T polymorphism and MS susceptibility or different clinical parameters in patients. In summary, carriers of IL-8 -251 T allele may have increased susceptibility to MS because of their differences in neuron survival or increased chances of viral persistence compared to carriers of A allele.