The purpose of this study was to evaluate the expression of S100A2 Ca2+-binding protein and its prognostic significance in the management of squamous cell carcinoma of the esophagus. Changes in cytosolic Ca2+ concentration control a wide range of cellular responses including cellular apoptosis. Intracellular S100 Ca2+-binding proteins are key molecules in transducing Ca2+ signaling. Among these, S100A2 has recently attracted major interest due to its stable expression in normal epithelia and down-regulation in some tumors. As a candidate tumor suppressor, expression of S100A2 has been proposed as a valuable prognostic marker in different tumors. We examined the clinical significance of S100A2 expression in 116 resected specimens of esophageal squamous cell carcinomas (ESCC) using immunohistochemistry. S100A2 was positive in 49 cases (42.2%) and its expression was significantly higher in large (p=0.01) and well differentiated tumors (p=0.013). Lymph node-positive tumors had a lower expression of S100A2 protein in comparison to the corresponding lymph node negative equivalents in each of the T stages, but the difference was statistically significant (p=0.041) only for the T1b tumors. S100A2 status became an independent predictor of patient survival (p=0.026) in lymph node-negative cases but not in node-positive cases. Evaluation of S100A2 protein expression may play an important role in the management of ESCC. The node-negative ESCC patients without S100A2 expression might be a high-risk group with poor survival and will need further attention to design appropriate adjuvant therapy.