As a tumor-associated antigen and a surface marker of breast cancer stem cells (BCSCs), epithelial cell adhesion molecule (EpCAM) plays an important role in not only cell adhesion, morphogenesis, metastases but also carcinogenesis. A non-synonymous C/T polymorphism (rs1126497) in exon3 of EpCAM causes a transition of 115 amino acid from Met to Thr. Another polymorphism (A/G, rs1421) in the 3'UTR causes loss of has-miR-1183 binding. A multiple independent case-control analysis was performed to assess the association between EpCAM genotypes and breast cancer risk. We observed that the variant EpCAM genotype (rs1126497 CT, and TT) was associated with substantially increased risk of breast cancer. Genotyping a total of 1643 individuals with breast cancer and 1818 control subjects in Eastern and Southern Chinese populations showed that rs1126497 CT + TT genotype had an odd ratio of 1.40 (95% confidence interval, 1.16-1.57) for developing breast cancer compared with CC genotype. The allele T increases the risk of breast cancer in a dose-dependent response manner (P (trend) < 0.001). Moreover, compared to breast cancer patients carrying the CC genotype, the EpCAM SNP rs1126497 CT or TT carrier was significantly associated with early breast cancer onset (P = 0.0023). However, no significant difference was found in genotype frequencies at the rs1421 A/G site between cases and controls. These findings suggest that M115T polymorphism in EpCAM may be a genetic modifier for developing breast cancer.