Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, characterized by neurological deficits. While the etiology of MS remains unclear, both genetic and environmental factors are known to play a role. Elevated levels of IL-12p40 have been observed in the cerebrospinal fluid and serum of MS patients, and it has been suggested that genetic variants in the IL-12B gene may contribute to MS susceptibility and/or pathogenesis. In this study, we investigated the association between MS and IL-12B gene rs17860508 and rs3212227 polymorphisms in the Turkish population. We identified two polymorphic regions in the IL-12B gene using bioinformatics tools and genotyped 351 MS patients and 221 healthy controls for these variants. Our results showed a significant association between the IL-12B rs17860508 polymorphism and MS, but no significant relationship between rs17860508 genotype distribution and allele frequency and MS age onset or MS subtypes. Genotype distribution and allele frequency of IL-12B rs3212227 polymorphism did not show any significant association with MS directly. However, AC genotype of IL-12B rs3212227 polymorphism in early-onset multiple sclerosis (EOMS) was a risk factor according to age of onset. Additionally, we observed a higher risk for the relapsing-remitting multiple sclerosis (RRMS) subtype in females. This is the first study to investigate the association between IL-12B polymorphisms and MS in the Turkish population.