CD40-CD40L interactions mediate T-dependent B cell response and efficient T cell priming. Therefore, genes encoding these molecules are attractive candidates for studies on autoimmune diseases, such as multiple sclerosis (MS), in which activated T and B cells are involved. Thus, we analyzed CD40 and CD40L mRNA expression in whole blood samples from MS patients and controls. Additionally, we examined the effect of three SNPs of CD40 (rs1883832C>T, rs11569343C>G, and rs752118C>T) and two SNPs of CD40L (rs3092923T>C and rs3092952A>G) on their mRNA expression. Our results showed that the rs1883832C>T SNP affects CD40 gene expression. Our analysis revealed that individuals possessing CT and TT genotypes (predisposing to MS) had decreased level of CD40 mRNA in comparison to those with CC. Moreover, we demonstrated the potential role of impaired CD40-CD40L interaction in developing of multiple sclerosis.