Abstract: Objective To investigate the expressions of grainyhead-like2 (GRHL2) and epidermal growth factor receptor (EGFR) in esophageal squamous cell carcinoma (ESCC) and their prognostic significance. Methods EnVision immunohistochemical method was used to detect the expressions of GRHL2 and EGFR in ESCC and adjacent normal squamous epithelium in 63 patients who received radical resection of esophageal cancer in Chinese PLA General Hospital and Hainan Branch Hospital. Results GRHL2 and EGFR expressed significantly higher in ESCC than in adjacent normal tissues (P < 0.05, respectively). The expression of GRHL2 was significantly correlated with tumor size, differentiation, lymph node metastasis and tumor staging (P < 0.05, respectively). The expression of EGFR was correlated with differentiation degree and tumor staging (P < 0.05, respectively). Spearman correlation analysis showed a negative correlation between GRHL2 and EGFR (r=-0.359, P=0.004). Kaplan-Meier survival curve analysis showed that disease free survival (DFS) and overall survival (OS) in patients with GRHL2 low expression were shorter than those with GRHL2 high expression (DFS:18.447±1.101 vs 38.976±1.7 months; OS:32.902±1.017 vs 54.015±2.208 months; P=0.000, respectively). On the contrary, DFS and OS in patients with EGFR high expression were shorter than those with EGFR low expression (DFS:22.190±1.564 vs 31.810±2.487 months; OS:36.522±1.931 vs. 48.168±3.331 months; P < 0.05, respectively). COX regression analysis showed that GRHL2, lymph node metastasis and tumor staging were independent prognostic factors for postoperative ESCC. Conclusion The abnormal expression of GRHL2 and EGFR may be involved in the occurrence and development of ESCC. Combined detection of GRHL2 and EGFR may help to determine the prognosis of patients with ESCC.