AIM:To investigate the expression and clinical signifi-cance of S100A2 mRNA and protein, p63 protein in esophageal squamous cell carcinoma (ESCC) and their roles in carcinogenesis and progression of esophageal carcinoma (EC).METHODS: Immunohistochemical staining (S-P method) for S100A2 and p63 protein were performed in 40 samples of ESCC and 40 samples of normal esophageal mucosa. In situ hybridization (ISH) was used to detect the expression of S100A2 mRNA.RESULTS: Expression of S100A2 mRNA in ESCC was positive in 77.5% of samples, which was lower than that in normal mucosa (100%) by ISH ( P = 0.002). The expression level of S100A2 mRNA was closely related to differentiation and and node-metastasis ( P = 0.012, P = 0.008). Expression of S100A2 protein was positive in 72.5% of ESCC samples and expression of p63 protein was positive in 37.5% of ESCC samples, and was lower than that in normal mucosa (100%) ( P = 0.000). The expression of S100A2 protein was correlated with the differentiation and node-metastasis ( P = 0.007, P =0.001), but no relationship was observed between the expression of p63 protein and clinical pathological manifestations. S100A2 protein was positively correlated with the expression of S100A2 mRNA, and negatively associated with the expression of p63 protein ( P = 0.000,P = 0.002).CONCLUSION: S100A2 and p63 protein both play important roles in the carcinogenesis of ESCC. An investigation into the combined expression of S100A2 and p63 may be helpful in early diagnosis and in evaluating the prognosis of ESCC.