Human leukocyte antigen‐E (HLA‐E) is one of the most extensively studied non‐classical MHC class I molecules that is almost non‐polymorphic. Only two alleles (HLA‐E*0101 and HLA‐E*0103) are found in worldwide populations, and suggested to be functional differences between these variants. The HLA‐E molecule can contribute to the escape of cancer cells from host immune surveillance. However, it is still unknown whether HLA‐E gene polymorphisms might play a role in cancer immune escape. To explore the association between HLA‐E alleles and the susceptibility to serous ovarian cancer (SOC), 85 primary SOC patients and 100 healthy women were enrolled. Here, we indicated that high frequency of HLA‐E*0103 allele existed in SOC patients by the allele‐specific quantitative real‐time PCR method. The levels of HLA‐E protein expression in SOC patients with the HLA‐E*0103 allele were higher than those with the HLA‐E*0101 allele using immunohistochemistry analysis. The cell surface expression and functional differences between the two alleles were verified by K562 cells transfected with HLA‐E*0101 or HLA‐E*0103 allelic heavy chains. The HLA‐E*0103 allele made the transfer of the HLA‐E molecule to the cell surface easier, and HLA‐E/peptides complex more stable. These differences ultimately influenced the function of natural killer cells, showing that the cells transfected with HLA‐E*0103 allele inhibited natural killer cells to lysis. This study reveals a novel mechanism regarding the susceptibility to SOC, which is correlated with the HLA‐E*0103 allele.