Objective To investigate the expression profile of CD27 in esophageal carcinoma and its potential gene regulatory pathways. Methods In this study, gene expression profiling interactive analysis (GEPIA) and cBio-Porta were used to analyze the differential expression and mutation of CD27 in esophageal cancer; GEPIA was used to perform Kaplan Meier curve analysis on the prognostic value of CD27 in patients with esophageal cancer and head and neck squamous cell carcinoma; functions and pathway enrichment of CD27 in esophageal cancer were performed by linkedomics through Pearson correlation coefficient analysis.Results The main type of CD27 mutation was amplification mutation in esophageal cancer. The expression of CD27 in esophageal carcinoma showed profound effects on TOR complex and various kinases (KIT-proto-oncogene receptor tyrosine kinase, transforming growth factor receptor 1, G protein-coupled receptor kinase 3). CD27 showed significant impact on overall survival of head and neck squamous cell carcinoma, and although it had no such effect on the overall survival of esophageal cancer, the patients with high expression had better overall survival. Conclusion The differential expression of CD27 may be a key factor in the occurrence and development of esophageal carcinoma. Our results suggest that the expression of CD27 might be a biomarker for esophageal cancer.