The prevalence of H. pylori infection has beenreported to be very high in duodenal ulcer (DU) disease,but the precise frequency and causes of H.pylori-negative DU are not well known. In somegeographical regions, however, a relatively low prevalenceof the infection has been described. Our aim was tostudy the frequency and causes of H. pylori-negative DUand to evaluate whether empirical H. pylori eradication therapy without confirmation of the infectionis justified. In all 774 consecutive patients with anendoscopic diagnosis of DU were studied prospectively.Exclusion criteria were associated diseases and previous gastric surgery. The use of NSAIDs,antibiotics (during the last month), and proton pumpinhibitors (during the last month) was evaluated bymeans of a specific questionnaire. At endoscopy, two biopsies from both antrum and corpus wereobtained in all 774 patients for histologic study(H&E stain). One sample from the antrum for rapidurease test, one sample each from the antrum and corpus for culture, and two duodenal biopsies forhistologic study were also obtained in the first 307patients. A [13C] urea breath test wascarried out in the remaining 467 patients. Patients were considered infected if any of the diagnostictests were positive and noninfected when all testsperformed were negative. Age (mean ± SD) was 46± 12 years, 70% were males. NSAID, antibiotic,and proton pump inhibitor use was described, respectively,in 8.9%, 5.8%, and 6.3% of the cases. H. pyloriinfection was demonstrated, overall, in 95.3% (95% CI:93.6-96.6%) of the patients. H. pylori prevalence increased up to 99.1% (98.1-99.6%) if patientstaking NSAIDs and/or antibiotics were excluded. Amongthe 36 H. pylori-negative patients, 20 (55%) were takingNSAIDs, 9 (25%) were taking antibiotics, and 1 (3%) both of them. Therefore, in only 6/774patients (0.8%) could DU disease be considered truly“idiopathic.” Differences were demonstratedbetween H. pylori-positive and -negative patients(univariate study; χ2) with regard to NSAIDintake (7% vs 58%; P < 0.0001) and previousantibiotic use (5% vs 28%; P < 0.0001). In themultivariate analysis (logistic regression), NSAID use(OR: 0.06; CI: 0.03- 0.13; P < 0.001) andantibiotic use (OR: 0.23; CI: 0.09-0.59; P < 0.01)were the only variables that correlated with H. pyloriinfection. The most important factors associated with H. pylori-negative DU are NSAIDs and priorantibiotic use, and if these agents are excluded, theprevalence of infection in our area is as high as 99%.Therefore, in DU patients not taking NSAIDs and living in areas where previous studies haveshown the prevalence of the infection in DU disease tobe very close to 100%, empirical H. pylori eradicationtherapy without confirmation of the infection may be justified.