Background: Through mounting genetic investigations, it has been established that IL12B and IL23R gene single nucleotide polymorphisms have significant associations with autoimmune diseases including inflammatory bowel disease, psoriasis, and ankylosing spondylitis. IL-12/IL-23 pathway plays a pivotal role in etiopathogenesis of multiple sclerosis (MS), suggested by studies both in patients and animal models. Methods: In a case-control study, 145 MS patients and 200 healthy subjects were genotyped for polymorphisms in IL12B and IL23R genes using Real-Time PCR allelic discrimination approach. Additionally, quantitative analysis of mRNA expression of IL12B in Peripheral Blood Mononuclear Cells from patients and controls was conducted through Real-Time PCR using the TaqMan Gene Expression Assay. Results: The rs6887695 single-nucleotide polymorphism (SNP) in IL12B gene showed an association with susceptibility to MS. GG genotype of this variation was more frequent in patients. mRNA expression of IL12B was upregulated in patients. Expression of IL12B mRNA in both MS patients collectively and those with GG genotype for rs6887695 SNP correlated negatively with onset age of MS patients. Conclusions: The GG genotype of rs6887695 SNP in IL12B gene plays a role in etiopathogenesis of MS.