In the context of additional radiation exposure, single nucleotide polymorphisms in the genes encoding the antioxidant system enzymes can contribute to the oxidative stress enhancement, damage to DNA, and therefore lead to the increase in the risk of malignant neoplasm (MN) development. The study was aimed to determine the association of the СYBA (rs4673), GPX1 (rs1050450), MPO (rs2333227), CAT (rs7943316), SOD2 (rs4880) polymorphic loci with the risk of MN development in individuals affected by low dose rate chronic radiation exposure considering intergenic interactions and the radiation dose. Two groups of individuals were included in the study: exposed individuals with no MNs — 384 people with the mean accumulated dose to the red bone marrow (RBM) of 796.95 ± 35.97 mGy; exposed individuals with the history of MNs — 227 people with the mean accumulated dose to RBM of 520.06 ± 38.72 mGy. Amplification of the rs4880, rs2333227, rs7943316, rs4673, rs1050450 polymorphic loci was performed with real time PCR. Compliance with the Hardy–Weinberg equilibrium was reported for all gene polymorphisms. It has been found that the rs4880*С (SOD2) and rs1050450*Т (GPX1) alleles are associated with the risk of MN development in accordance with the dominant (OR = 1.49 (1.02–2.18), р = 0.04) and recessive (OR = 2.00 (1.11–3.62), р = 0.02) inheritance modes, respectively. An interfactor interaction model with the 100% reproducibility and 66% accuracy (р = 0.001) has been obtained that includes the SOD2 (rs4880), СYBA (rs4673) polymorphisms and the factor of accumulated dose to RBM. Thus, polymorphic loci of the genes regulating the oxidative status of the cells are associated with the increased risk of MN development in individuals, who have experienced chronic radiation exposure with predominant exposure of RBM.