Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. It is a clinically heterogeneous disorder especially in terms of disease severity. Current investigations suggest that genes and gene-gene interactions not only influence on susceptibility to MS but also affect the disease severity. In this study, we investigated the contribution of the HLADRB1*1501 allele and single nucleotide polymorphism (SNP) in CD24 gene and also combined genotypes of the HLADRB1*1501 and CD24 SNP to disease severity in Iranian MS patients. We have reported previously that the HLA- DRB1*1501 allele and the CD24v/v genotype associated with disease susceptibility and some other studies proposed that HLA-DRB1*1501 allele be associated with MS severity. In this study, the results showed a significant difference in the Multiple Sclerosis Severity Score (MSSS) of the nine different genotypes (F=2.838, P=0.007). Subsequent analysis revealed a statistically significant difference in the MSSS between the MS patients who were carriers of HLA-DRB1*1501/1501 and those who were not carriers of HLA-DRB1*1501/1501 genotypes (P=0.04). Moreover, the MS patients carrying combined genotypes of the HLA- DRB1*1501/x-CD24 v/v had statistically severe disease than the patients who did not carry the HLA- DRB1*1501- CD24 v/v (P=0.047). In conclusion, our findings suggest that, HLA-DRB1*1501/1501 and bigenic genotypes of the HLA- DRB1*1501/x- CD24 v/v may influence on disease severity in Iranian MS patients.