This study aimed to evaluate the receptor activator of nuclear factor-kappa B (RANK) expression statuses of esophageal squamous cell carcinoma (ESCC) patients, high-grade intraepithelial neoplasia (HGIN), low-grade intraepithelial neoplasia (LGIN), and normal esophageal tissues (NETs) in Chinese Han and Kazakh ethnic, as well as the correlation of RANK expression with clinicopathological characteristics. RANK immunohistochemical analysis was conducted to investigate the expression of RANK in 113 ESCC, 36 HGIN, 63 LGIN, and 98 NETs from Han ethnic patients and in 196 ESCC and 76 NETs from Kazakh ethnic patients. The associations of RANK expression with ethnic and clinicopathological characteristics were examined using chi(2)-test. Upregulated RANK expression was detected in both Han and Kazakh ethnic ESCC tissues, compared with NETs (P = 1.11x10(-5), 0.001, respectively). RANK expression was significantly increased during malignant transformation from normal epithelium into LGIN (P = 2.84x10(-7)) and HGIN (P = 7.83x10(-6)) tissues in Han ethnic patients. The increased expression of RANK also correlated with lymph node metastasis in Kazakh ethnic ESCC patients (P = 0.019). By contrast, no significant correlation existed between RANK expression and clinicopathological characteristics of Han ethnic ESCC patients. Furthermore, Kaplan-Meier survival analysis showed that ESCC patients with higher expression of RANK protein had significantly worse prognosis than ESCC patients with low or no expression (P = 0.001). In conclusion, this study is the first to identify RANK overexpression as a novel esophageal cancer marker in both Kazakh and Han ethnic ESCC patients. The results support the association of RANK with ESCC across ethnicities. In summary, RANK could be a therapeutic target in ESCC patients.