Objective: NF-E2-related factor 2 (Nrf2) is activated in several human malignancies. However, the role ofNrf2 in gastric cancer (GC) remains incompletely understood. In this study, we therefore analyzed associationsof Nrf2 expression status with clinical features and chemotherapeutic resistance in GC. Materials and Methods:A total of 186 samples from GC patients who underwent gastrectomy were used for prognostic assessment.A further 142 samples from GC cases who received first-line combination chemotherapy were applied forinvestigation of chemoresistance. The Nrf2 expression was evaluated by immunohistochemistry in GC samples,and its relationship with clinicopathological parameters and chemotherapy sensitivity was analyzed. The effectof Nrf2 gene silencing on chemotherapy resistance was also examined by cell viability assay in vivo. Results: Ofthe 186 patients with GC, 104/186 (55.9%) showed high expression for Nrf2. The overexpression of Nrf2 was anindependent predictor of overall survival [OS, hazard ratio (HR) 3.9; P=0.011] and disease-free survival (DFS,HR 4.3; P=0.002). The gene silencing of Nrf2 reduced resistance to cell death induced by 5-FU in GC cell lines. Conclusion: Our data show that Nrf2 is an independent prognostic factor in GC. Furthermore, Nrf2 confersresistance to chemotherapeutic drug 5-FU in GC cells. Taken together, Nrf2 is a potential prognostic markerand predictive for 5-FU resistance in GC.