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BACKGROUND The aim of this study was to elucidate the correlation of high-mobility group protein A2 overexpression with gastric cancer prognosis and compare its prognostic power with that of pre-existing markers. METHODS Malignant tissues from 396 patients with gastric cancer who underwent gastrectomy from 2008 to 2012 were examined. High-mobility group protein A2 expression was assessed by immunohistochemistry and the sensitivity and specificity for predicting disease progression and overall survival of high-mobility group protein A2 and the prognostic biomarkers p53, Ki-67, human epidermal growth factor receptor 2, cyclooxygenase-2, and epidermal growth factor receptor were compared. RESULTS A total of 95 samples (24.1%) showed high-mobility group protein A2 overexpression, which was related to advanced stage, undifferentiated histology, and lymphatic and perineural invasion. Additionally, high-mobility group protein A2 overexpression was an independent prognostic factor in multivariate analysis for disease progression and overall survival. Based on Kaplan-Meier survival analysis disease progression and overall survival, the high-mobility group protein A2-overexpressing patients showed worse survival. The recurrence pattern of peritoneal dissemination was more frequently observed in high-mobility group protein A2-positive group. Moreover, chemoresistance was more frequently observed in the high-mobility group protein A2-positive group. High-mobility group protein A2 exhibited a better ability for predicting disease progression and overall survival than other markers, and the prognostic power was enhanced when high-mobility group protein A2 was used with these markers. CONCLUSION High-mobility group protein A2 overexpression is associated with chemoresistance and a propensity for carcinomatosis peritonei after surgery in patients with gastric cancer. The power to predict the prognosis of patients with gastric cancer can be enhanced with the use of preexisting biomarkers and high-mobility group protein A2.