Multiple sclerosis (MS) is a chronic neurological disease of unknown etiology, but a genetic basis for the disease is undisputed. We have reported that CD24 is required for the pathogenicity of autoreactive T cells in experimental autoimmune encephalomyelitis, the mouse model of MS. Here we investigate the contribution of CD24 to MS by studying single-nucleotide polymorphism in the ORF among 242 MS patients and 207 population controls. This single-nucleotide polymorphism results in replacement of alanine (CD24a) with valine (CD24v) in the mature protein. We found that the CD24v/v renders a >2-fold increase in the relative risk of MS in the general population (P = 0.023). Among familial MS, the CD24v allele is preferentially transmitted into affected individuals (P = 0.017). Furthermore, 50% of CD24v/v patients with expanded disability status scale 6.0 reached the milestone in 5 years, whereas the CD24a/v (P = 0.00037) and CD24a/a (P = 0.0016) patients did so in 16 and 13 years, respectively. Moreover, our data suggest that the CD24v/v patients expressed higher levels of CD24 on peripheral blood T cells than did the CD24a/a patients. Transfection with CD24a and CD24v cDNA demonstrated that the CD24v allele can be expressed at higher efficiency than the CD24a alleles. Thus, CD24 polymorphism is a genetic modifier for susceptibility and progression of MS in the central Ohio cohort that we studied, perhaps by affecting the efficiency of CD24 expression on the cell surface.