Objective: To explore the relationship between tradiotherapeutic sensitivity and p53 gene expression in esophageal carcinoma. Methods: A retrospective study was performed to collect 93 cases of surgically resected specimens of esophageal squamous cell carcinoma, and the X-ray classification of each resected specimen was determined. Immunohistochemistry was used to detect the expression of p53 in different X-ray specimens. Five fields of view were selected under a 400-fold optical microscope for counting, and brown-yellow particles in the nucleus were positive for p53. The expression level of p53 was determined by double-blind reading by two senior pathologists. Results: There were 11 cases of umbrella type and intracavitary type, of which 2 cases were positive for p53 gene expression, 9 cases were negative. Sixty-two cases of medullary type, with 23 positive cases and 39 negative cases. There were another 20 cases of constricted and ulcerated type, 15 cases were positive, and 5 cases were negative. There was a statistically significant difference in the expression level of p53 compared with different X-ray types (P<0.01). There was a significant difference in the effective rate of p53 positive and negative patients (P<0.05). There was no significant difference in the treatment efficiency between HIF-1α and bcl-2 positive and negative patients (P>0.05). Conclusion: The expression of p53 is significantly increased in esophageal squamous cell carcinoma, and its expression is negatively correlated with radiosensitivity. p53 is not overexpressed, and its radiosensitivity is higher. Conversely, p53 overexpression is less sensitive to radiotherapy, and is a genetic mutation. The sensitivity of radiotherapy in patients with esophageal cancer may be one of the reference indicators for the detection of p53 gene expression.