p53-binding protein 1 (P53BP1), a central transducer of DNA-damage signals to p53, is required for both intra-S-phase and G2-M checkpoints, suggesting that these two proteins may work together in the p53-mediated transcriptional activation and DNA damage-repair signaling pathways. Because the p53-binding region of 53BP1 maps to the C-terminal BRCT domains, which are homologous to those found in the breast cancer protein BRCA1, we hypothesized that genetic variation in P53BP1 and p53 may contribute to breast cancer predisposition. To test this hypothesis, we simultaneously genotyped single nucleotide polymorphisms of T-885G, Glu353Asp, and Gln1136Lys in P53BP1 and Arg72Pro in p53 in a case-control study of 404 breast cancer cases and 472 cancer-free controls. We found that the P53BP1 variant genotypes (alleles) of T-885G and Gln1136Lys were associated with a significantly increased risk of breast cancer among p53 Pro/Pro carriers (OR=2.36, 95% CI 1.16-4.83 for -885TG/GG; OR=2.24, 95% CI 1.15-4.37 for 1136Gln/Lys+Lys/Lys and OR=2.82, 95% CI 1.15-6.94 for >4 variant alleles of these 3 loci). In addition, the variant genotypes of above 3 loci of P53BP1 were significantly associated with elevated risk of progesterone receptor (PR) negative breast cancer, and the T-885G and Gln1136Lys with estrogen receptor (ER) negative breast cancer. Furthermore, we found a significant gene-gene interaction between P53BP1 Gln1136Lys and p53 Arg72Pro variants in relation to breast cancer, and the OR of interaction for the presence of both P53BP1 1136Gln/Lys+Lys/Lys and p53 72Arg/Pro+Pro/Pro genotypes was 1.93 (95% CI 1.06-3.52) (P=0.031 for interaction). These findings indicate that the SNPs in P53BP1 and p53 jointly contribute to breast cancer risk, particularly ER (-) or PR (-) breast cancer, and the p53 Arg72Pro polymorphism may serve as a risk modifier. Further functional studies are needed to confirm our findings.