Multiple sclerosis (MS) is a chronic autoimmune disease with neurodegenerative consequences, characterized by inflammatory areas, demyelination and axonal degeneration. The etiology of this disease is still not fully elucidated due to the complex relationship between environmental factors, genetic predisposition and viral infection, whereby these factors can play a role in the risk for the development of the disease to a greater or lesser extent and are not mutually exclusive. One of the genes associated with susceptibility to MS is the MTHFR gene. Polymorphic gene variants, MTHFR C677T and MTHFR A1298C, result in reduced activity of the enzyme encoded by the corresponding gene. This disrupts the balance of folate and methionine metabolism, which causes increased levels of neurotoxic homocysteine and free radicals, which damage myelin, and reduced levels of S-adenosylmethione, necessary for remyelination. Previous studies in different populations have shown inconsistencies in the results in an attempt to link polymorphisms with a predisposition to MS. This research was conducted using the PCR-RFLP method on 200 MS patients and 200 control subjects in order to define the role of MTHFR polymorphisms in the predisposition to MS and the clinical expression of the disease. Processing the results revealed that the MTHFR C677T and MTHFR A1298C polymorphisms do not contribute to an increased risk for MS. However, an association was found between the presence of the T allele of the MTHFR C677T polymorphism and an increased disease progression index, and the potential influence of the C allele of the MTHFR A1298C polymorphism on the duration of the disease. Analysis of the interaction between polymorphisms indicates an increased risk of the disease for people with the combination of CC/AC genotypes and a possible reduced risk for those with the CC/CC combination. In conclusion, the studied polymorphisms do not contribute to susceptibility to MS, but they can modify the expression of the disease, which must be taken with caution considering the limited number of subjects with certain combinations of polymorphisms.