As enhanced chromosomal radiosensitivity (CRS) results from non- or misrepaired double strand breaks (DSBs) and is a hallmark for breast cancer and single nucleotide polymorphisms (SNPs) in DSB repair genes, such as non homologous end-joining (NHEJ) genes, could be involved in CRS and genetic predisposition to breast cancer. In this study, we investigated the association of five SNPs in three different NHEJ genes with breast cancer in a population-based case-control setting. The total patient population composed of a selected group of patients with a family history of the disease and an unselected group, consisting mainly of sporadic cases. SNP analysis showed that the c.2099-2408G>A SNP (XRCC6) has a significant, positive odds ratio (OR) of 2.81 (95% confidence interval (CI): 1.30–6.05) for the heterozygous (He) and homozygous variant (HV) genotypes in the selected patient group. For the c.-1310 C>G SNP (XRCC5) a significant OR of 1.85 (95%CI: 1.01–3.41) was found for the He genotype in the unselected patient group. On the contrary, the HV genotype of c.1781G>T (XRCC5) displays a significant, negative OR of 0.43 (95%CI: 0.18–0.99) in the total patient population. The He+HV genotypes of the c.2099-2408G>A SNP (XRCC6) also showed high and significant ORs in the group of “radiosensitive,” familial breast cancer patients. In conclusion, our results provide preliminary evidence that the variant allele of c.-1310C>G (XRCC5) and c.2099-2408G>A (XRCC6) are risk alleles for breast cancer as well as CRS. The HV genotype of c.1781G>T (XRCC5) on the contrary, seems to protect against breast cancer and ionizing radiation induced micronuclei. © 2007 Wiley-Liss, Inc.