Objectives: To analyze the expression and clinical significance of p75NTR in esophageal squamous cell carcinoma. Methods: Sixty patients with esophageal squamous cell carcinoma who underwent surgical resection in our hospital between January 2017 and January 2018 were selected as the study subjects. The content of the study was in accordance with medical ethics and approved by the medical ethics committee, and patients understood and signed an informed consent form. The clinical data of all patients were analyzed retrospectively. The positive rate of p75NTR in lymph node metastasis-positive patients, lymph node metastasis-negative patients and patients with invasion of the muscle layer was detected and statistically analyzed. Results: Lymph node metastasis-positive patients had a p75NTR-positive rate of 100.00% (30/30), which was significantly higher than that of lymph node metastasis-negative patients (20.00% (6/30)) (P < 0.05) The p75NTR-positive rate in patients with infiltration of the muscular layer was 73.33% (20/30), which was significantly higher than that of patients with infiltration of the whole layer (43.33% (13/30) (P < 0.05). Conclusions: The high expression of p75NTR in esophageal squamous cell carcinoma tissue can indicate the invasion depth of the cancerous tissue and lymph node metastasis, and the clinical introduction of the p75NTR index can be the basis for an effective prognosis prediction in patients with esophageal squamous cell carcinoma.