Objective: To compare the expression of HER2, RKIP, and ERK in adenocarcinoma of esophagogastric junction (AEG) and distal gastric adenocarcinoma(DGA), and explore the differences in the pathogenesis of AEG and DGA. Methods: The expression of HER2, RKIP and ERK in AEG, DGA and normal gastric mucosal tissue were detected by immunohistochemistry, and the relationship between HER2, RKIP, and ERK with clinical pathological characteristics and their correlation were analyzed. Results: The positive expression rate of HER2 in AEG was higher than that in DGA, and the difference was statistically significant (P<0.05). The positive expression rates of RKIP in AEG and DGA were lower than that in normal gastric mucosal tissue, while the positive expression rates of ERK were higher than that in normal gastric mucosal tissue (P<0.05). In AEG, the positive expression rate of RKIP was lower in the high/moderate differentiation group and lymph node metastasis group, while the positive expression rate of ERK was higher in the low differentiation group, serosa invasion group, and lymph node metastasis group (P<0.05); HER2 expression was positively correlated with ERK expression (r=0.352, P=0.007), while RKIP expression was negatively correlated with ERK expression (r=-0.521, P=0.000).In DGA, the positive expression rate of RKIP was lower in the poorly differentiated group and lymph node metastatic group, while the positive expression rate of ERK was higher in the lymph node metastatic group (P<0.05); RKIP expression was negatively correlated with ERK expression (r=-0.287, P=0.021). Conclusion: The positive expression rate of HER2 in AEG is higher than that in DGA, and the high expression of ERK is more closely related to the clinicopathological characteristics of AEG patients. The expression of RKIP is closely related to the differentiation degree and lymph node metastasis of AEG and DGA. The expression of HER2, RKIP, and ERK in AEG and DGA is different, indicating that the regulatory mechanism of MAPK signaling pathway is not completely consistent in different locations of gastric adenocarcinoma.