Abstract Gastric cancer has high prevalence and high modality worldwide. For many years, few improvements in the efficacy of treatments were reported for advanced gastric cancer settings. Although a novel molecular target agent trastuzumab, in combination with chemotherapy, prolongs overall survival time in advanced gastric cancer, resistance to this drug still exists among human epidermal growth factor receptor-2 (HER2) positive patients. HER2 and erythropoietin receptor (EPOR) downstream signaling pathway have some common factors like Akt, Erk and STATs. Also there exist evidences that EPOR may express on some solid tumors and probably promote tumor progression. So it is reasonable for us to hypothesis that HER2 and EPOR may be co-expressed in the same gastric cancer cell and if so, EPOR signaling pathway may overlaps that with HER2 and promotes HER2 induced signal transduction to cell proliferation. In clinical settings, a stimulation of EPOR will play antagonistic effects on trastuzumab-induced anti-tumor activity to HER2-positive gastric cancer patients. Co-expression of EPOR and HER2 is a predictive factor for resistance of trastuzumab in gastric cancer.