BACKGROUND AND AIM: Recently, statins have appeared to have additional benefits beyond their lipid lowering effects, which has led to the interest in the use of this class of drugs outside the realm of cardiovascular disease. Simvastatin (SIM) is a commonly prescribed statin with anti-inflammatory and antioxidant properties. Excessive generation of oxygen-derived free radicals (ODFR) and proinflammatory mediators has been implicated in the pathogenesis of gastric ulcers. This investigation aimed to study the effect of SIM on experimentally induced gastric acid secretion and ulcer formation. METHODS: Adult Wistar rats were divided into experimental groups containing six animals. Acid secretion studies were undertaken using pylorus-ligated rats pretreated with SIM (20, 40, and 60 mg/kg). The effect of orally administered SIM was also studied on indomethacin- and ethanol-induced gastric ulcers. The levels of myeloperoxidase (MPO), non-protein sulfhydryls (NP-SH), nitric oxide (NO), antioxidant enzymes, and gastric wall mucus were measured in the glandular stomach of rats following ethanol-induced gastric lesions. RESULTS: Administration of SIM significantly and dose-dependently inhibited the volume of gastric secretion and the acidity. Pretreatment with SIM significantly reduced the formation of indomethacin- and ethanol-induced gastric lesions. The antiulcer activity of SIM was associated with significant attenuation of adverse effects of ethanol on gastric wall mucus, NP-SH and MPO. SIM modified the gastric NO levels and reversed the ethanol-induced decrease in glutathione-S-transferase and increase in superoxide dismutase and catalase. CONCLUSIONS: These findings clearly suggest the involvement of proinflammatory agents and ODFR in the pathogenesis of gastric lesions. The gastroprotective effects of SIM are mediated by inhibition of neutrophils activity, reduction of oxidative stress, and maintenance of vascular integrity. This study was conducted in rats; its relevance to human gastric ulcers is not known and warrants further study.