Stanniocalcin-1 (STC1) is a secreted glycoprotein hormone and highly expressed in various types of human malignancies. Although evidence points to the role of STC1 in human cancers, the clinical significance of STC1 expression in esophageal cancer has not been well established. Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were performed to assess the expression of STC1 in the cancer cell line TE8 and esophageal cancer tissues from 229 esophageal squamous cell carcinomas (ESCC). Surgically-resected tissue sections were immunostained for potential regulators of STC1 expression, hypoxia-inducible factor-1α (HIF-1α) and p53. Marked increase in STC1 mRNA and protein expression was noted in TE8 cells cultured under hypoxic conditions. Overexpression of STC1 mRNA was noted in ESCC tumors compared to normal counterparts. Positive immunohistochemical staining for STC1 protein was observed in 38.9% of patients, and correlated significantly with advanced pT status (p=0.019), poor prognosis [overall survival (p<0.0006) and disease-free survival (p<0.0002) of ESCC patients who had undergone curative surgery]. Positive staining for HIF-1α and p53 proteins in ESCC did not correlate with STC1 expression. The results showed marked induction of STC1 expression under hypoxia in cultured cells and in esophageal cancer cells and that overexpression of STC1 was an independent prognostic factor in patients with esophageal cancer who had undergone curative surgery. STC1 is a potentially useful biomarker for ESCC treatment.