Background and Objective: P53 is a suppressive gene that plays a key role in DNA repair and apoptosis. The purpose of this study was to investigate the effect of P53 protein over-expression and some clinicopathological factors on the esophageal squamous cell carcinoma (SCC) response to neoadjuvant chemoradiotherapy. Patients and Methods: In this retrospective cohort study, 44 patients with localized esophageal SCC undergoing neoadjuvant chemoradiotherapy (cisplatin + 5FU and 40 Gy in 20 fractions of irradiation) and surgery were evaluated. Pretreatment specimens were immunohistochemically assessed for p53 over-expression and scored according to the frequency of stained cells. The pathologic response in resected specimens was categorized as follows: complete response (CR), no evidence of malignant cell; partial response (PR), small foci of malignant cells and negative lymph nodes and minor response, macroscopic residual tumor or positive lymph nodes. Results: It was found out that p53 protein over-expression exists in 29 cases (65.9%). Following chemoradiotherapy, CR and PR were found in 9 (20.5%) and 19 cases (43.2%) respectively. There were also no significant association between tumor response and clinicopathological features such as sex (p = 1), age (p = 0.82), dysphagia grade (p = 0.82) and longitudinal length of the tumor (p = 0.59). No significant correlation was found between p53 expression and pathological response to preoperative chemoradiotherapy (p = 0.94). Conclusion: These findings suggest that p53 protein expression is not reliable for predicting the response to neoadjuvant chemoradiotherapy. There were also no correlations between pathological response to chemoradiotherapy and clinical features such as age, sex, dysphagia grade and longitudinal diameter of the tumor.