Management of the gastro-toxicity of non-steroidal anti-infl ammatory drugs (NSAIDs) remains a crucial problem, because the commercially available anti-ulcer drugs have side eff ects and are often expensive. Hence, the potential of a new water-soluble GPx mimic, DL- trans -3, 4-dihydroxy-1-selenolane (DHS_red) in healing the indomethacin-induced stomach ulceration in mice was examined. Administration of indomethacin (18 mg/kg, p. o. ) induced ulceration in the glandular portion of the gastric mucosa, accompanied by increased lipid peroxidation (1.3-fold, p < 0.001) and protein oxidation (1.5-fold, p < 0.001), depletion of thiol-defense (42.5%, p < 0.01), plasma total antioxidant status (53.4%, p < 0.001) and mucin (47.5%, p < 0.01), as well as reduced expressions of cyclooxygenases and prostaglandin synthesis (54.7%, p < 0.001) in the gastric tissues of mice. Daily oral administration of DHS red (2.5 mg/kg) or omeprazole (Omez) (3 mg/kg) for 3 days respectively produced ∼ 74% and 69% ( p < 0.001 ) healing of the acute gastric ulceration. The test samples also signifi cantly reversed all the adverse eff ects of indomethacin on the biochemical parameters. Apparently, the gastric ulcer healing action of DHS_red and Omez was due to their antioxidant action and their ability to protect mucin and augment PG synthesis by upregulation of the COX isozymes. The results suggested that the non-toxic and inexpensive compound, DHS_red , may be a good candidate for further evaluation as a potent anti-ulcer drug.