Programmed death-ligand 1 (PD-L1) expression either indicates immune inhibitory status or concurrent immune response. Although the relationship between PD-L1 and clinical outcomes has been studied widely in recent years, its role in prognosis of esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we assessed the significance of PD-L1 in ESCC and its association with epidermal growth factor receptor (EGFR) and radiation response. We found that PD-L1 was present both on the surface of tumor cells and tumor-infiltrating immune cells. Patients with tumor-infiltrating immune cell PD-L1 expression had better survival. PD-L1 expression on immune cells was an independent prognostic factor for patients with ESCC. PD-L1 expression either on tumor-infiltrating immune cells or tumor cells was negatively associated with EGFR expression. EGFR/PD-L1 pairs could separate the survival between EGFR low/PD-L1 positive and EGFR high/PD-L1 negative groups. In ESCC cell lines with EGFR high expression, PD-L1 expression was induced significantly when EGFR signaling was activated by radiation and was dramatically inhibited by an EGFR tyrosine kinase inhibitor. In conclusion, tumor-infiltrating immune cell PD-L1 expression is an independent prognostic factor for ESCC, and the association between EGFR and PD-L1 is vital to determining survival. It is important to consider radiotherapy-induced imbalance of pro-tumor and anti-tumor immune response. A combination of radiotherapy and PD-L1-targeted therapy could be a promising therapeutic strategy for ESCC patients.