To investigate the association of human leukocyte antigen-E (HLA-E) gene polymorphisms and plasma soluble HLA-E (sHLA-E) levels with genetic susceptibility to breast cancer in Zhangjiakou women of Han nationality.HLA-E typing was performed in 200 patients with breast cancer and 228 healthy controls from Zhangjiakou area by means of polymerase chain reaction-sequence-specific priming (PCR-SSP). Simultaneously, sHLA-E was detected by ELISA.We found two alleles of HLA-E: HLA-E*0101 and HLA-E*0103, and three genotypes, namely HLA-E*0101/HLA-E*0101, HLA-E*0101/HLA-E*0103 and HLA-E*0103/HLA-E*0103. The frequencies of HLA-E*0103 allele and HLA-E*0103/HLA-E*0103 genotype showed a significant difference between healthy controls and patients with breast cancer. The HLA-E*0103/HLA-E*0103 genotype significantly increased the risk for breast cancer. Plasma levels of sHLA-E showed no significant difference in breast cancer patients and controls. While in breast cancer patients with HLA-E*0103/HLA-E*0103 genotype, plasma levels of sHLA-E were significantly elevated compared with those in healthy controls. HLA-E genotypes and sHLA-E levels had no obvious relationship with tumor grading.HLA-E gene polymorphisms are associated with the development of breast cancer in Zhangjiakou women of Han nationality. HLA-E*0103/HLA-E*0103 genotype is probably susceptible genotype for breast cancer, while plasma sHLA-E level probably has no association with breast cancer susceptibility.