CD27 as a marker of memory B cells is belong to the tumor necrosis factor receptor (TNFR) superfamily, CD27 is ligated by CD70, they can co-stimulate T-cell growth and differentiation through their interaction. Uncertainty surrounds CD27's function in esophageal cancer (EC). This study investigated the role of CD27 in the prognosis of EC using the TCGA, cbioportal, linkedomics and GEPIA databases as well as the proliferation assay was applied. CD27 differential expression may be a key factor in the development of EC. different level of CD27 expression in EC has profound impacts on TOR complex, and many kinds of kinase (KIT proto-oncogene receptor tyrosine kinase, transforming growth factor beta receptor 1, and G protein-coupled receptor kinase 3.), as well as the cell membrane, and survival analysis revealed that it had a significant impact on both the overall survival and disease-free survival of EC. CD27 overexpression will suppress the viability of the KYSE150 and TE3 cells. Our findings suggested that the degree of CD27 expression could serve as an esophageal cancer prognosis biomarker.