Xuechao Liu,1,2,* Pengfei Xu,1,3,* Haibo Qiu,1,2,* Jianjun Liu,1,2 Shangxiang Chen,1,2 Dazhi Xu,1,2 Wei Li,1,2 Youqing Zhan,1,2 Yuanfang Li,1,2 Yingbo Chen,1,2 Zhiwei Zhou,1,2 Xiaowei Sun1,2 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 2Department of Gastric and Pancreatic Surgery, 3Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Purpose: We sought to determine whether human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) expression were independent prognostic factors for gastric cancer (GC).Patients and methods: A total of 678 consecutive patients with GC undergoing curative surgery between October 2010 and December 2012 had resected tissue examined for HER2 and VEGF expression using immunohistochemistry. Immunohistochemical expression of HER2 was analyzed using the DAKO-HercepTest™ and scored according to published reports. VEGF expression was calculated by multiplying the score for the percentage of positive cells by the intensity score. We defined positive expression as a score of 1+, 2+, or 3+, and a score of 0 was defined as negative expression. We compared these results to clinicopathological characteristics, including overall survival (OS).Results: Multivariate analysis revealed that HER2 expression was independently associated with shorter OS (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.10–2.18; P=0.01) and with higher tumor–nodes–metastasis stage (HR, 3.88; 95% CI, 2.67–5.64; P<0.001) in patients with GC. VEGF expression was not associated with OS (HR, 1.25; 95% CI, 0.86–1.82; P=0.24). HER2 expression was still identified as an independent prognostic factor in Stage II–III patients treated with surgery and adjuvant chemotherapy (P=0.004) but not in patients who received surgery alone (P=0.61). Among patients with Stage III GC, those without HER2 expression survived longer with adjuvant chemotherapy (median 43.9 vs 32.2 months, respectively; P=0.04), whereas those with HER2 expression did not (median 37.1 vs 33.9 months, respectively; P=0.67).Conclusion: HER2 expression is independently associated with OS in GC, especially in patients who are at higher risk and receive adjuvant chemotherapy after curative resection. HER2 expression may have important clinical utility in directing adjuvant treatment for Stage III GC patients. Keywords: adjuvant chemotherapy, human epidermal growth factor receptor 2, prognosis, vascular endothelial growth factor, VEGF