BACKGROUND: MicroRNAs (miRNAs) have been proven to be critical players in many different types of tumors including esophageal squamous cell carcinoma (ESCC). OBJECTIVE: This study aimed at investigating the correlation of miR-138 expression and clinical outcome of patients with ESCC. METHODS: A total of 168 serum samples and 128 fresh cancer tissues as well as their corresponding adjacent non-cancerous tissues were collected. Real-time PCR was performed to evaluate the clinical value of miR-138 in ESCC. RESULTS: Our results showed that tissue and serum miR-138 levels were both significantly reduced in ESCC compared to their respective controls. Tissue miR-138 levels were highly correlated with serum miR-138 levels. Serum miR-138 differentiated patients with ESCC from healthy controls with high accuracy. In addition, reduced tissue/serum miR-138 levels were correlated with unfavorable clinicopathological parameters including T stage, lymph node metastasis and TNM stage. ESCC patients with lower tissue/serum miR-138 levels had shorter five year overall survival compared with those with higher tissue/serum miR-138 levels. Finally, downregulation of miR-138 was demonstrated to be an independent prognostic risk factor for ESCC. CONCLUSIONS: In conclusion, both tissue and serum miR-138 levels are reduced in ESCC, and might be promising prognostic biomarkers for ESCC.