Abstract Background: Duodenal ulcer is a major health problem that many scientists are interested in its management to avoid complications and the side effects of the usual treatments. Aim of Study: Demonstrating and comparing the possible effects of chronic administration of omega-three polyunsatu-rated fatty acids, leptin, and vinegar on duodenal ulcer in male albino rats, with the possible underlying mechanisms involved in such effects. Material and Methods: Four groups of experimental animals were used, with 16 rats in each: the control group (I), w-3 fatty acids fed (II), Leptin fed (III), and vinegar fed (IV). For each group, we estimated, from the gross duodenal exam-ination, the ulcer score and index, and percentage ulcer protection. Also, histology appearance of the duodenal mucosa was examined together with the measurement of duodenal HCO3-amount, CCK, and secretin gene expression. Results: In comparison to control group, the ulcer score and index were diminished significantly while percentage ulcer protection, HCO3-amount, and expression of secretin and CCK genes were increased significantly in rat groups fed with w-3, vinegar, and leptin. Vinegar has a more protective effect than w-3 and leptin. Conclusion: We conclude that vinegar, w-3, and leptin have a protective effect against induction of duodenal ulcer, and vinegar had a better effect against ulcer induction followed by w-3 and finally leptin.