Multiple sclerosis (MS) is a demyelinating disease of the central nervous system in which there is a multifocal damage to the nerve tissue. Additionally, the literature emphasizes the excessive accumulation of iron in the central nervous system of patients, which is negatively correlated with their psychophysical fitness. Iron metabolism genes polymorphisms may modulate iron deposition in the body and thus affect the clinical course of MS. We aimed to assess the frequency of HAMP, TFR2, and TF polymorphisms in MS patients and their impact on the clinical course of the disease. The studied polymorphisms were identified by the Real-Time PCR using TaqMan technology. Neurological assessment by means of EDSS scale was conducted. This cross-sectional study included 176 patients, with the mean age of onset of symptoms at 30.6 years. The frequency of alleles of the studied polymorphisms was as follows: (a) HAMP rs10421768: A 75.9% (n = 267), G 24.1% (n = 65), (b) TF rs1049296: C 89.2% (n = 314), T 10.8% (n = 38), (c) TF rs3811647: A 39.8% (n = 140), G 60.2% (n = 212), (d) TFR2 rs7385804: A 59.1% (n = 59.1%), C 40.9% (n = 144). In the codominant inheritance model of TF rs1049269, it was shown that people with the CT genotype scored statistically significantly lower points in the EDSS scale at the time of diagnosis than those with the CC genotype (CC Me = 1.5, CT Me = 1.0 p = 0.0236). In the recessive model of TF inheritance rs3811647, it was noticed that the primary relapses were significantly more frequent in patients with at least one G allele compared with those with the AA genotype (AG + GG = 81.2%, AA = 18.8%, p = 0.0354). In the overdominant model rs7385804 TFR2, it was shown that among patients with the AA genotype, multiple sclerosis occurs significantly more often in relatives in a straight line compared with people with the AC and CC genotypes (AA = 100.0%, AC + CC = 0.0%, p = 0.0437). We concluded that the studied polymorphisms might affect the clinical course of MS.