Objective To investigate the relationship and clinical significance between the expressions of RegIV and EGFR, PI3K proteins in gastric adenocarcinoma. Methods S-P Immunohistochemistry was used to detect the expression of RegIV and EGFR, PI3K proteins in pathological tissue with 63 cases with e gastric adenocarcinoma and tumor-adjacent normal esophageal tissue. Results The positive expression rates of RegIV and EGFR, PI3K proteins in 63 cases with gastric adenocarcinoma tissue 50.7% (32/63)、68.3% (43/63) 、60.3% (38/63) respectively, were significantly different from the positive expression rates of tumor-adjacent normal esophageal tissues 19.0% (12/63)、20.6% (13/63)、9.5% (6/63)respectively(P<0.05); The expression of RegIV was significantly correlated to differentiation degree (P<0.05)and the expression of PI3K protein was significantly correlated to differentiation degree, infiltrative depth, TNM stage and lymph node metastasis(P<0.05). The expression of Akt protein was significantly correlated to lymph node metastasis (P<0.05). There was positive correlation between the expression of RegIV/PI3K, RegIV/Akt and PI3K/Akt proteins in esophageal squamous cell carcinoma and the value of Spearman coefficient correlation were 0.284,0.305 and 0.423 (P<0.05)． Conclusions RegIV may play an important role in tumorigenesis and tumor progression by activating PI3K/Akt signaling pathway.