Objective: To detect the expression of NRAGE protein in esophageal squamous cell carcinoma and investigate the relationship between NRAGE and therapeutic effect of radiotherapy. Methods: The expression level of NRAGE in 44 patients with esophageal squamous cell carcinoma was evaluated by immunohistochemistry and statistically analyzed along with clinical data by using multivariate analysis using Cox regression model. Results: The overall expression level of NRAGE protein in esophageal squamous cell carcinoma (P=0.025) and the expression level of NRAGE nuclear protein (P=0.008) were negatively correlated with short-term efficacy. In terms of the overall expression level of NRAGE protein, the 3-year survival rates in the strongly positive group and the positive weakly positive group were 16% and 36%(P=0.198). As for the expression of NRAGE nuclear protein, the 3-year survival rates in the strongly positive group and the positive+ weakly positive group were 0% and 41%(P<0.001). Multivariate analysis using Cox regression model demonstrated that as for the expression of NRAGE nuclear protein, the risk of death in the strongly positive group was significantly higher than those in the positive+ weakly positive group (P=0.002). Conclusion The overall expression level of NRAGE protein in the esophageal cancer is negatively correlated with the short-term efficacy of radiotherapy, whereas it is not correlated with long-term survival rate. The strongly positive expression level of NRAGE nuclear protein is negatively correlated with the short-term efficacy of radiotherapy and the long-term survival rate, prompting that NRAGE may be a molecular indicator for predicting radiation resistance and even the efficacy of radiotherapy for esophageal squamous cell carcinoma