The relationship between Helicobacter pylori infection and aspirin (ASA)-induced gastropathy and gastric adaptation to ASA remains unclear. We compared gastric damage and adaptation after repeated exposures to ASA in the same subjects without H. pylori infection and those infected by H. pylori before and after eradication of this H. pylori. Twenty-four volunteers in two groups (A and B), without H. pylori infection (group A) and with H. pylori infection (group B) before and after H. pylori eradication, were given ASA 2 g/day or placebo for 14 days. Mucosal damage was evaluated by endoscopy and gastric microbleeding; mucosal prostaglandin (PG) E2 generation and luminal transforming growth factor (TGF)α were determined on days 0, 3, 7 and 14 of the ASA course. In all subjects, ASA-induced gastric damage reached a maximum on day 3. In H. pylori-positive subjects this damage was maintained at a similar level up to the 14th day of observation. Following H. pylori eradication, the damage was significantly lessened at day 14, as revealed by both endoscopy and microbleeding, and was accompanied by increased mucosal release of TGFα. Prostaglandin E2 generation was significantly higher in H. pylori-positive subjects than after H. pylori eradication, but ASA treatment resulted in greater than 90% reduction of this generation independent of H. pylori status. Gastric adaptation to ASA is impaired in H. pylori-positive subjects but eradication of this bacterium restores this process.