Preliminary evidence suggests that eradication of Helicobacter pylori (H. pylori) may lead to prolonged remission of duodenal ulcer (DU). The aim of this study was to assess the long-term effect of eradication of H. pylori on the natural history of DU. Fifty-one patients with endoscopically proven duodenal ulcers, who were found to have H. pylori infection on histology and culture, and who were successfully eradicated of H. pylori with combination treatment of colloidal bismuth subcitrate and antibiotics, were studied. All patients were endoscoped at entry, 4 wk after cessation of treatment and again at 1 yr or sooner, if symptoms recurred. At each endoscopy, two antral biopsies were taken and assessed histologically and microbiologically for evidence of H. pylori infection. Recurrence of H. pylori infection occurred in 18/51 patients (35.3%) and, of these, 12 patients had evidence of recurrent peptic disease (five DU, seven duodenitis). In contrast, of the 33 who remained negative for H. pylori at 1 yr, none developed evidence of recurrent DU. Overall, DU recurrence occurred in 5/51 patients (11.7%), and occurred only in patients reinfected with H. pylori. This relapse rate compares favorably with patients on maintenance H2-receptor antagonist treatment. These results lend further support to the hypothesis that antral reinfection with H. pylori is associated with relapse of DU.