Nowadays, against the backdrop of a global increase in cancer incidence, the search for prognostic markers to assess individual risks is particularly relevant. Early identification of altered DNA methylation patterns may serve as a reliable indicator of malignant transformation and be used for diagnostic purposes. The objective of this study was to assess the methylation level of CpG dinucleotides in the promoter regions of DNA repair genes (AKT1, DDB2, GADD45A, XPC and XRCC3) in the blood of chronically exposed individuals who subsequently developed cancers. The study was conducted in individuals who were affected by chronic low dose-rate exposure in 1950-1960s in the Southern Urals. The main group included exposed individuals in the latent period of cancer development-104 people, the comparison group consisted of exposed individuals without cancers-188 people. The methylation level was assessed in bisulfite-converted DNA samples using methylation-specific high-resolution melting. It was established that in exposed individuals from the main group, there was a statistically significant decrease in the methylation level in the AKT1 and GADD45A gene promoter, relative to the comparison group (4.37 versus 7.23%, p < 0.001 and 10.73 versus 19.58%, p < 0.001, respectively). As for the XRCC3 gene, there was an increase in the methylation level of CpG dinucleotides in the promoter in individuals from the main group relative to the comparison group (5.38 versus 6.18%, p < 0.001). When the prognostic potential of methylation parameters of the AKT1, GADD45A, XRCC3 gene promoters was assessed for the purposes of early diagnosis of cancer development risk, it was found that when these loci were analyzed together, the AUC was 0.89 (95% CI: 0.85-0.93) at p < 0.001.