In conclusion, our results show that there was a positive correlation between EGFR and PD-L1 expression in ESCC patients, and for patients without surgery, EGFR and PD-L1 co-expression could predict poor ORR and inferior survival, indicating a subset of patients who may benefit from a combination of targeted therapy against EGFR and PD-L1, which may expand the population benefiting from immunotherapy and reduce the occurrence of hyper progressive diseases. This evidence concerns the gene CD274 and esophageal squamous cell carcinoma.