Current methods have limited accuracy in predicting survival and stratifying patients with gastric cancer for appropriate treatment. We sought to identify protein signatures of gastric cancer for classification and prognostication. The Protein Pathway Array (initial study) and Western blot (confirmation) were used to assess the protein expression in a total of 199 fresh frozen gastric samples. There were 56 paired samples divided into a training set (n ؍ 37) and a validation set (n ؍ 19) for the identification of differentially expressed proteins between tumor and normal tissues. There were 56 tumor samples used to identify proteins correlating with tumor and nodal staging. All 93 tumor samples were used to identify candidate proteins for predicting survival. We confirmed the survival prediction of the candidate proteins by using an additional cohort of gastric cancer samples (n ؍ 50). There were 22 proteins differentially expressed between normal and tumor tissues. Nine proteins were selected to build the predictor to classify normal and tumor samples. Ten proteins were differentially expressed among different T stages and four of these were associated with invasive behavior. An additional four proteins were associated with lymph node metastasis. Two proteins were identified as independent risk factors for overall survival. This study indicated that some dysregulated signaling proteins could be selected Gastric cancer is the fourth most common malignancy and ranked as the second leading cause of cancer death worldwide.1 The geographic distribution of incidence and mortality of gastric cancer varies remarkably worldwide. Areas with high incidence include Japan, Korea, China, Eastern Europe, and parts of Latin America. The mortality of gastric cancer has declined in past decades, mainly due to early detection by gastric endoscopy. 2 However, unlike that of other common cancers, the prognosis for most gastric cancer is poor and has improved little for the past several decades. Despite recent advances in chemotherapy and surgical techniques, the overall 5-year survival rate is lower than 40%.3 Perplexingly, the prognosis varies widely in patients with stage II or III disease for undetermined biological reasons.