It is generally accepted that overexpression of p53 protein is associated with poor prognosis in gastric, lung, and other types of cancer. However, the prognostic significance of p53 aberrations in esophageal cancer remains unclear. This is the largest study (n = 266) examining clinical and prognostic features of p53 immunohistochemical expression in esophageal squamous cell carcinoma. In 139 (52%) esophageal tumors, nuclear immunoreactivity for p53 protein was detected. p53 aberrant expression was not associated with sex, age, preoperative treatment, TNM stage, or histological grade. Furthermore, p53 expression did not correlate with disease-free survival (P = 0.73) or overall survival (P = 0.62). In addition, no significant modification effect by any of the covariates in the survival analysis was observed (all P > 0.15). In conclusion, our large-scale study demonstrates that p53 expression has no impact on the prognosis of esophageal squamous cell carcinoma.