Purpose¡G Many single nucleotide polymorphisms (SNPs) have been found to be associated with breast cancer but their SNP interactions are seldom addressed. In this study, we focused on the joint effect for SNP combinations of seven CXCL12-related genes involved in major cancer related pathways. Patients and Methods¡G SNP genotyping was determined by PCR-restriction fragment length polymorphism (RFLP) in this study (case = 220, control = 334). Different numbers of combinational SNPs with genotypes called the pseudo-haplotypes from different chromosomes were used to evaluate their joint effect on breast cancer risk. Results¡G Except for VEGF rs3025039-CT, none of these SNPs was found to individually contribute to breast cancer risk. However, for two combined SNPs, the proportion of subjects with breast cancer was significantly low in the pseudo-haplotype with CC-GG genotypes in rs2228014-1801157 (CXCR4-CXCL12) compared to those with non-CC-GG genotypes. Similarly, the pseudo-haplotype of rs12812942-rs2228014-rs3025039 (CD4-CXCR4-CXCL12) And rs12812942-rs3136685-rs2228014 -rs1801157(CD4-CCR7-CXCR4-CXCL12)with specific genotype pattern (AT-CC-CC and AT-AG-CC-GG) among three and four combinational SNPs were significantly low in breast cancer occurrence. More SNP combinations larger than five SNPs were also addressed and shown the similar effect. After controlling for age, comparing to their corresponding non-pseudo-haplotypes, the estimated odds ratios for breast cancer ranged between 0.20 and 0.71 for specific pseudo-haplotypes with two to seven SNPs. Conclusion¡G We have identified the potential combined CXCL12-related SNPs with genotypes that were protective against breast cancer and may have an impact on identification of a low risk population for the development of breast cancer.