The purpose of the present study was to identify a biomarker that can predict the response to preoperative chemoradiotherapy (PCRT) in esophageal cancer patients. Twenty-five serum samples collected from patents with esophageal cancer before PCRT (responder = 13, non-responder = 12) were analyzed by quantitative proteomics, and 248 proteins were identified. Among them, the serum levels of leucine-rich alpha-2-glycoprotein 1 (LRG1) were significantly different ( p < 0.01) and well discriminated (area under the curve ( AUC ) of the receiver operating characteristic (ROC) curve >0.8) between responder and non-responder groups. The combination of LRG1 with C-reactive protein (CRP) and soluble interleukin-6 receptor (sIL-6R), which were previously reported as biomarkers predicting PCRT response, further improved the predictive performance, providing an AUC of greater than 0.9. The present results suggest that LRG1 and its combination with CRP and sIL-6R are promising biomarker candidates to predict response to PCRT in esophageal cancer patients.