Background: Maintenance use of nonsteroidal anti-inflammatory drugs (NSAIDs) is often complicated by gastropathy. In non-NSAID users, eradication of Helicobacter pylori is associated with decreased mucosal inflammation, and may halt the progression to atrophy and intestinal metaplasia, but the continuous use of NSAIDs may interfere with these processes. Goal: To investigate the effect of H. pylori eradication on gastric mucosal histology during long-term NSAID use, with and without gastroprotective therapy. Study: Patients were eligible for inclusion if they were on long-term NSAIDs and were H. pylori-positive on serologic testing. Patients were randomly assigned to either eradication or placebo. Gastritis was assessed according to the updated Sydney classification for activity, chronic inflammation, gastric glandular atrophy, intestinal metaplasia, and H. pylori density. Results: Biopsy specimens were available for histology of 305 patients. Or these, 48% were on chronic gastroprotective medication. Significant less active gastritis, inflammation. and H. pylori density was found in the eradication group compared with the placebo group in both Corpus and antrum (P < 0.001). In the corpus, less atrophy was found in the eradication group Compared with the placebo group. Conclusions: H. pylori eradication in patients on long-term NSAID therapy leads to healing of gastritis despite ongoing NSAID therapy.