Radiotherapy is the major approach and is well tolerated in locally advanced esophageal squamous cell carcinoma (ESCC). And nowadays, no effective biological markers have been identified for predicting the prognosis of patients with ESCC. Platelet-derived growth factor (PDGF) is associated with a poor prognosis of various malignancies. The present study aimed to assess the effect of PDGF-BB on radiotherapeutic responses of ESCC and the underlying mechanisms of its roles in ESCC. Serum from 68 cases that received neoadjuvant or radical radiotherapy was obtained before and during radiotherapy. Gene expression analyses were validated by enzyme linked immunosorbent assay. The prognosis of patients with significantly reduced PDGF-BB was probably better than that of the others found in the progression-free survival and overall survival groups. Depletion of PDGFB significantly suppressed the proliferation, invasion and migration of cancer cells. Inhibiting PDGFB induced cellular apoptosis and promoted the sensitivity to ionizing radiation (IR). Furthermore, IR inhibited PDGF-BB-induced migration by blocking the PI3K/AKT pathway in ESCC cells. We found that the expression of PDGF-BB provided a possible model for predicting ESCC radiotherapy. It can also be used as a prognostic indicator for locally advanced ESCC that was treated by radiotherapy.