Esophageal cancer is a common human malignant tumor with high mortality. Glandular epithelial markers, such as CAM5.2, can be expressed in esophageal squamous cell carcinoma (ESCC), but the clinical significance of these cells in ESCC remains elusive.Immunohistochemical analysis of CAM5.2 was performed on 604 ESCC specimens using tissue microarray. Our study design and study population used retrospective cohorts based on the hospital information system and pathological information management system which included medical information, date of admission, procedures undergone, registration, examinations, and medication.In total, positive staining of CAM5.2 was 145 of 604 (24%). Statistical analysis showed that the expression of CAM5.2 had no relationship with sex, age, tumor differentiation, tumor size, tumor-node-metastasis (TNM) classification, and lymph node metastasis, but it was significantly associated with poor prognosis of overall survival (P = .0041) and disease-free survival (P = .0048) in ESCC patients.Herein, we report for the first time that the high expression of the CAM 5.2 is an independent predictor of poor prognosis in patients with ESCC.