Background: Metformin has been recently reported to provide anti-infiammatory or antitumor activity in colitic and colitic tumor animal models through inhibition of nuclear factor kappaB (NF-κB) signaling. There is no evidence of metformin inducedattenuation of gastric mucosal infi ammation by alcohol. The aim of this study is to investigate the effect of metformin on NF-κB signaling and endoplasmic reticulum (ER) stress in human gastric epithelial cells in vitro and on ethanol-induced acute murine gastritis in vivo. Methods: Human gastric epithelial MKN-45 cell lines were pretreated with metformin and then stimulated with tumor necrosis factor-a (TNF-a). Interleukin-8 (IL- 8) expression was determined by real-time RT-PCR. NF-κB DNA-binding activity in the nuclear extracts was assessed by electrophoretic mobility shift assay (EMSA). The molecular marker of ER stress, including CHOP and XBP1 was evaluated using PCR. In the ethanol-induced acute gastritis model, mice were given absolute ethanol (50 mg/kg, 250 mg/kg) by oral gavage with or without metformin. Using the extracted gastric tissue, macroscopic assessment, histological evaluation and immunohistochemical staining for phospho-IκB kinase (IKK) was performed. Results: Metformin signifi cantly inhibited the upregulated expression of IL-8 in MKN- 45 cells stimulated with TNF-a in a dose dependent manner. Pretreatment of MKN- 45 cells with metformin decreased activity of NF-κB in TNF- a -stimulated cells. CHOP and XBP1 mRNA expression was enhanced in the presence of TNF-a, and it was dampened by pretreatment of metformin. Administration of metformin signifi cantly attenuated the severity of ethanol-induced acute murine gastritis, as assessed by macroscopic and histological evaluation of gastric mucosal damage. Conclusions: These results indicate that metformin inhibits NF-κB activation and ER stress in gastric epithelial cells and that it ameliorates experimental murine gastritis. These results suggest that metformin is a potential gastroprotective agent.