BackgroundRecent studies have demonstrated that acetyl‐CoA synthetase 2 (ACSS2) plays a critical role in cancer cell survival; however, the role of ACSS2 in gastric carcinogenesis has not been determined.MethodsWe investigated the expression of ACSS2 in human gastric cancer (GC) tissues using immunohistochemistry, and analyzed its clinicopathological correlation and prognostic relevance.ResultsAmong 350 GCs, 219 cases (62.6%) were classified as ACSS2‐low, whereas 131 cases (37.4%) were ACSS2‐high. Loss of ACSS2 expression (ACSS2‐low) was more frequently observed in undifferentiated histology (P = 0.002), in cases with MLH1‐loss (P = 0.003), and in cases with SIRT3‐low (P < 0.001). The ACSS2‐low cases showed significantly lower mean disease‐free survival (DFS, 68.5 vs. 81.8 months; P = 0.025) and overall survival (OS, 73.5 vs. 86.6 months; P = 0.029). In multivariate analysis, loss of ACSS2 expression was identified as one of the independent prognostic factors predicting worse DFS (HR: 1.547, P = 0.018) and OS (HR: 1.476, P = 0.036).ConclusionsWe revealed that the loss of ACSS2 expression is a reliable independent poor prognostic factor in GC. Our results may expand our understanding of the involvement of glucose metabolism, including the role of ACSS2, in the pathogenesis of GC. J. Surg. Oncol. 2015;112:585–591. © 2015 Wiley Periodicals, Inc.