OBJECTIVE: To investigate the expressions of signal transduction and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1-alpha (HIF-1α) in esophageal squamous cell carcinoma (ESCC), and their potential roles in the pathology of ESCC. PATIENTS AND METHODS: Tumor tissues and clinical data of 202 ESCC patients treated in our hospital from January 2011 to June 2013 were collected. Expressions of STAT3 and HIF-1α in tumor tissues and normal esophageal tissues were detected by immunohistochemical S-P method. Correlation of STAT3 and HIF-1α with clinicopathological parameters and prognosis of ESCC were analyzed. RESULTS: STAT3 was positively expressed in 82/202 ESCC tissues, with a positive expression rate of 40.59%, and HIF-1α was positively expressed in 142/202 ESCC tissues, with a positive expression rate of 70.30%. Both STAT3 and HIF-1α were highly expressed in ESCC tissues than those normal esophageal tissues, showing statistically significant differences (p<0.05). The expression of STAT3 was positively correlated with that of HIF-1α in ESCC tissues (r=0.401, p<0.05). Overall survival (OS) and disease-free survival (DFS) of ESCC patients with positive STAT3 and HIF-1α expression were markedly worse than those with negative expression (p<0.05). STAT3 and HIF-1α were related to the infiltration depth (T stage) of ESCC (p<0.05). Univariate and multivariate analyses revealed that the expression of STAT3 was associated with OS and DFS (p<0.05) and was an independent prognostic factor for ESCC. CONCLUSIONS: High expressions of STAT3 and HIF-1α are closely related to ESCC. STAT3 is an independent prognostic risk factor for ESCC, and HIF-1α may be a poor prognostic survival factor for ESCC, both of which can be used as indicators to predict the prognosis of ESCC patients.