The study goal was to examine the association of three polymorphisms in the XRCC1 gene (Arg194Trp, Arg280His, and Arg399Gln) involved in repairing DNA damage produced by ionizing radiation, a known breast cancer (BC) risk factor, with BC incidence and the possibility of developing an adverse radiotherapy response. Genomic DNA from 254 BC cases, 70 of whom were adverse radiotherapy responders [radiation-sensitive breast cancer (RS-BC) patients], and 312 female blood donors were genotyped using either TaqMan technology or variant specific restriction enzyme digestion. Neither the exon 6 codon 194Trp allele [BC versus controls: odds ratio (OR), 1.03; 95% confidence interval (CI) 0.62-1.67] nor the exon 10 codon 399Gln allele (BC versus controls: OR, 0.95; 95% CI, 0.74-1.23) alone was associated with an increased BC risk. The exon 9 codon 280His allele was associated with an increased risk (OR, 1.8; 95% CI, 1.07-3.05) in both the radiation-sensitive and non-radiation-sensitive cases and, in combination with the 399Gln allele, was found more frequently in cases than in controls (OR, 2.54; 95% CI, 1.04-6.22). The exon 6 194Trp allele was associated with the risk of developing an adverse response to radiotherapy (RS-BC versus non-radiation-sensitive BC: OR, 1.98; 95% CI, 0.92-4.17). This allele, in combination with the 399Gln allele, was found more frequently in RS-BC cases than in the non-radiation-sensitive BC cases (OR, 4.33; 95% CI, 1.24-15.12). Distinct combinations of XRCC1 polymorphisms appear to be associated with either an increased BC risk or the possibility of developing an adverse radiotherapy response seen in some BC patients.