Papillary thyroid carcinoma (PTC) etiologically occurs as a radiation-induced or sporadic malignancy. Genetic factors contributing to the susceptibility to either form remain unknown. In this retrospective case–control study, we evaluated possible associations between single-nucleotide polymorphisms (SNPs) in the candidate DNA damage response genes (ATM, XRCC1, TP53, XRCC3, MTF1) and risk of radiation-induced and sporadic PTC. A total of 255 PTC cases (123 Chernobyl radiation-induced and 132 sporadic, all in Caucasians) and 596 healthy controls (198 residents of Chernobyl areas and 398 subjects without history of radiation exposure, all Caucasians) were genotyped. The risk of PTC and SNPs interactions with radiation exposure were assessed by logistic regressions. The ATM G5557A and XRCC1 Arg399Gln polymorphisms, regardless of radiation exposure, associated with a decreased risk of PTC according to the multiplicative and dominant models of inheritance (odds ratio (OR)=0.69, 95% confidence interval (CI) 0.45–0.86 and OR=0.70, 95% CI 0.59–0.93 respectively). The ATM IVS22-77 T>C and TP53 Arg72Pro SNPs interacted with radiation (P=0.04 and P=0.01 respectively). ATM IVS22-77 associated with the increased risk of sporadic PTC (OR=1.84, 95% CI 1.10–3.24) whereas TP53 Arg72Pro correlated with the higher risk of radiogenic PTC (OR=1.80, 95% CI 1.06–2.36). In the analyses of ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC genotype strongly associated with radiation-induced PTC (OR=2.10, 95% CI 1.17–3.78). The GG/CC/GG/GG genotype displayed a significantly increased risk for sporadic PTC (OR=3.32, 95% CI 1.57–6.99). The results indicate that polymorphisms of DNA damage response genes may be potential risk modifiers of ionizing radiation-induced or sporadic PTCs.