OBJECTIVE: The proportion of Helicobacter pylori - negative duodenal ulcer disease appears to be increasing. Data on clinical outcome and prognosis in this subgroup are lacking. METHODS: Two hundred seventy-six duodenal ulcer patients randomized, irrespective of H. pylori status, to either eradication therapy or maintenance omeprazole (double-blind, double-dummy design) for 1 yr were studied. Patients were followed up for a total of 2 yr, with visits performed every 2 months the first year and every 6 months the following year. Endoscopies for assessment of ulcer relapse were done at 6 and 12 months or in the event of symptomatic relapse. H. pylori status was assessed by culture, immunohistochemistry, and urea breath test at entry, at 6, 12, and 24 months or at failure. The primary endpoint was discontinuation, irrespective of reason. Patients were considered H. pylori negative if all three tests were negative. Patients were considered H. pylori - positive if any of the three diagnostic tests were positive. Study staff were blinded to H. pylori results. RESULTS: Thirty-two (12%) patients were H. pylori negative at entry. There were no differences according to H. pylori status for a number of clinical and demographic characteristics. However, H. pylori - negative patients had a shorter history of ulcer symptoms and were more likely to be NSAID users (19% vs 1%, p < 0.001). Only 28% of the H. pylori - negative patients completed the study, as compared with 40% of H. pylori - positive patients (p = 0.0005). The main reasons for the poorer prognosis in H. pylori - negative patients were relapse of ulcer/ulcer not healed (35% vs 26%) and relapse of severe dyspepsia symptoms without ulcer relapse (16% vs 7%). H. pylori - negative patients randomized to eradication therapy left the study early compared with H. pylori - negative patients randomized to long-term omeprazole therapy. Outcome in omeprazole-treated patients did not differ according to H. pylori status (p = 0.3). CONCLUSIONS: Clinical characteristics in H. pylori - negative and positive duodenal ulcer patients differ little. Clinical outcome over 2 yr is significantly poorer in H. pylori - negative patients, especially if treated empirically with eradication therapy. These results suggest that H. pylori infection should be assessed in all duodenal ulcer patients before treatment is decided.