The aim of this study is to investigate the association of IκBα promoter polymorphisms with the development of Multiple Sclerosis (MS) disease in Iranian population. One hundred and fifty patients with MS along with 150 unrelated healthy controls were enrolled in this study. The IκBα -881A/G (rs3138053), -826C/T (rs2233406) and -519C/T (rs2233408) polymorphisms were determined by the polymerase chain reaction/restriction fragment length polymorphism method. This study demonstrated that the genotype frequencies of IκBα -881A/G and -826T/T, and allele frequencies of IκBα-881G were significantly higher in patients with MS with respect to as compared to the controls. We also found that the estimated haplotype frequency of IκBα promoter -881G-826T-519C was significantly increased in the patient with MS in comparison with that of the healthy individuals. This study reveals that polymorphisms in the IκBα promoter (-881 A/G, -826 C/T) are strongly associated with the susceptibility of Iranian MS patients.