Multiple myeloma (MM) is a plasma cell malignancy that is currently incurable. Finding new targets and designing drugs are crucial for the treatment of MM. The two datasets (GSE6691 and GSE39754) are used to screen highly expressed antigen on MM cells. HLA-E was an ideal target for it was a hub gene, and also located in one of the key clusters. Highly expression of HLA-E mRNA on MM cells was also confirmed by real-time qPCR testing the MM patients' samples in Shengjing hospital. Crystal structure of HLA-E was obtained from Protein Data Bank (PDB ID: 3CDG) which was used to design targeting peptides with Molecular Operating Environment software. By analyzing interaction between CD94/NKG2A and HLA-E, a peptide with twelve amino acids was screened as a model peptide. Peptides library was constructed by randomly replaced non-key amino acid. Peptide-protein docking method was used to identify high affinity peptides. PEPTIDE 1-3 and model peptide were synthesized and identified the affinity to HLA-E by flow cytometer and confocal laser microscopy. At last, PEPTIDE3 (NALDEYCEDKNR) was found with the highest affinity. Taking all, HLA-E is a new treatment target, and PEPTIDE 3 is an ideal high affinity target-binding peptide candidate.