X-ray repair cross-complementing 1 (XRCC1) plays a critical role in base excision repair and genetic variations of XRCC1 may be associated with cancer susceptibility. We tested this hypothesis by examining the contribution of polymorphism in the regulatory region of XRCC1 -77T>C to risk of breast cancer in 995 patients and 1,004 controls. We found this polymorphism was associated with an increased risk of breast cancer, with an OR of 1.25 (95% CI, 1.00-1.56) for the -77TC genotype and 2.55 (95% CI, 1.11-5.86) for the -77CC genotype compared with the -77TT genotype. Haplotype analysis combining the -77T>C with three well-studied non-synonymous polymorphisms (Arg194Trp, Arg280His, and Arg399Gln) showed that only the -77C-containing haplotype was associated with the risk. Moreover, the C allele had more than 3-fold decreased luciferase expression compared with the T allele in breast cancer cell line MCF-7 (P < 0.001). A meta-analysis of seven publications with a total 2,888 cancer cases and 3,177 controls demonstrated that -77C was significantly associated with cancer risk, with an OR of 1.34 (95% CI, 1.18-1.51) for the TC genotype and 1.53 (95% CI, 1.14-2.07) for the CC genotype compared with the TT genotype. In conclusion, these findings indicated that XRCC1 -77T>C polymorphism may be a genetic determinant for developing breast cancer.