Background: Gastric adenocarcinoma (GAC) is a serious disease with poor outcome. Discovering novel molecular targeted therapies is a recent point of research to improve prognosis. One of the newly discovered targets is the receptor tyrosine kinases (RTKs); it is a member of trans-membrane receptors which had important roles in proliferation and apoptosis. RTKs were found to have different expression patterns in several malignancies. HER2 neu which is a member of HER family is a proto-oncogene that is formed of four receptor tyrosine kinases. Erythropoietinproducing hepatocellular (Eph) molecules are major RTKs members and one of those molecules is EphA2 which has many different functions in cancer as tumor initiation, progression, angiogenesis and spread. We aimed to explore the expression patterns of both HER2 neu and EphA2 in GAC patients using immunohistochemistry, and to correlate their expressions with clinico-pathological factors and prognosis of our patients Methods: HER2 neu and EphA2 expressions were assessed in sections from forty blocks of paraffin which were diagnosed as GAC. Then we analyzed the correlations between their expressions and disease outcome of GAC patients. Results: HER2 neu and EphA2 positive expressions in GAC were positively correlated with tumor grade and stage (p<0.001 and p=0.002 respectively), inadequate response to therapy (p<0.001 and p=0.002 respectively), increase recurrence rate of GAC (p=0.002), and with poor survival (p<0.001). Conclusion: GAC patients with high expressions of both HER2 neu and EphA2 had unfavorable prognosis.