Abstract: Reflux esophagitis (RE), a major gastrointestinal disorder results from excess exposure of the esophageal mucosa to acidic gastric juice or bile-containing duodenal contents refluxed via an incompetent lower esophageal sphincter. Recent studies implicated oxygen derived free radicals in RE induced esophageal mucosal damage resulting in mucosal inflammation. Thus, control over free radical generation and modulation of inflammatory responses might offer better therapeutic effects to counteract the severity of RE. In this context we investigated the effect of melatonin against experimental RE in rats. Melatonin pretreatment significantly reduced the haemorrhagic lesions and decreased esophageal lipid peroxidation aggravated by RE. Moreover, the depleted levels of superoxide dismutase and glutathione observed in RE were replenished by melatonin signifying its free radical scavenging properties and antioxidant effects resulting in the improvement of esophageal defense mechanism. Further melatonin repressed the upregulated levels of expression of proinflammatory cytokines like, TNF-α, IL-1β and IL-6 in RE. However, increased levels of the anti-inflammatory cytokine IL-10 remained unaltered after melatonin administration signifying its immunomodulatory effect through suppression of Th1-mediated immune responses. The involvement of receptor dependent actions of melatonin against RE were also investigated with MT2 receptor antagonist, luzindole (LUZ). LUZ failed to antagonize melatonin’s protective effects against RE indicating that melatonin mediated these beneficial effects in a receptor-independent fashion. Thus, esophageal mucosal protection elicited by melatonin against experimental RE is not only dependent on its free radical scavenging activity but also mediated in part through its effect on the associated inflammatory events in a receptor-independent manner.