In this study, we explored the relationship between GPNMB, EGFR, p-PI3K, and Ki-67 in ESCC for the first time and preliminarily confirmed the roles of GPNMB, EGFR, p-PI3K, and Ki-67 in ESCC and their impact on prognosis. This evidence concerns the gene EGFR and esophageal squamous cell carcinoma.