DNA double-strand breaks (DSBs) may lead to genomic instability and cancer if unrepaired. Nijmegen breakage syndrome 1 (NBS1) protein is one of the key proteins that participates in recognition and repair of DSBs in humans. We hypothesized that polymorphisms of NBS1 are associated with breast cancer risk. We selected three NBS1 haplotype-tagging polymorphisms (i.e. 924T>C, 8360G>C and 30537G>C) to represent all common (>or=5%) haplotypes reported in the National Institute of Environmental Health Sciences database and to reconstruct haplotypes. In a hospital-based case-control study of 421 non-Hispanic white patients with sporadic breast cancer (C polymorphism. Furthermore, the derived haplotypes were associated with risk in a dose-response manner as the number of variant (risk) alleles (i.e. 8360C, 924C or 30537C) increased (adjusted OR = 1.07, 95% CI = 0.78-1.46 for 1-2 variant alleles; adjusted OR = 2.47, 95% CI = 1.48-4.14 for 3-6 variant alleles; P(trend) = 0.006). These findings suggest that NBS1 polymorphisms and haplotypes may contribute to the etiology of sporadic breast cancer in young non-Hispanic white women. Large studies are warranted to confirm these findings.