Recent studies have reported elevated plasma homocysteine and reduced folate and vitamin B levels in patients with multiple sclerosis (MS). In this study, we aimed to investigate the association between MS and the following four DNA polymorphisms: MTR A[2756]G, MTHFR C[677]T, MTHFR A[1298]C and MTRR A[66]G. The DNA polymorphisms were genotyped in 80 patients with confirmed MS and 80 healthy control age- and gender-matched subjects using PCR-RFLP approach. Our results show that the frequency of the T/T genotype homozygotes for the MTHFR C[677]T polymorphism was significantly higher in patients than in controls (p = 0.04, OR: 3.16, 95% CI: 1.23-8.17). In turn, the A/A genotype of the MTHFR A[1298]C polymorphism was more frequent in controls than in patients (41.3% vs. 32.5%, p = 0.04). There were no differences in distribution of genotypes for the MTR A[66]G and MTR A[2756]C polymorphisms between patients with MS and controls (p > 0.05). Our findings suggested that the MTHFR C[677]T and MTHFR A[1298]C gene polymorphisms might be associated with MS as genetic factors influencing the risk of the disease.