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Objective To explore the expression and clinical significance of cystatin S(CST4) in patients with esophageal squamous cell carcinoma(ESCC)in Kazakhs. Methods Totally 49 specimens from Kazakh ESCC patients who received surgical treatment were collected. RT-qPCR and immunohistochemical methods were used to detect CST4 expression in cancer tissues and adjacent tissues. Chi-square(χ2) test was used to analyze the relationshipbetween CST4 expression and the clinicopathological parameters. Kaplan-Meier method and Cox regression model were used to estimate the correlation between CST4 expression and overall survival. Results CST4 mRNA expression in ESCC tissues was higher than that in adjacent tissues (P＜0.05). CST4 protein expression in ESCC tissues (53.1%, 26/49) was higher than that in adjacent tissues (28.2%, 11/39) (χ2=5.506, P＜0.05). The expression of CST4 was significantly associated with lymph node metastasis (P＜0.05) and TNM stage (P＜0.01). Those with high CST4 expression had higher lymph node metastasis rate and later TNM stage. Univariate survival analysis showed that CST4 expression level(P＜0.01), invasion depth (P＜0.05) and TNM stage (P＜0.01) were associated with overall survival. Multivariate survival analysis showed that the CST4 expression (P＜0.05) and the invasion depth (P＜0.05) were independent prognostic factors for survival of ESCC patients. Conclusions CST4 expression is related to the occurrence, progression and prognosis of ESCC so it can be a potential prognostic marker for ESCC in Kazakhs.