NSAIDs constitute an important risk factor for peptic ulcer and are one of the most commonly prescribed drug. The aim of the study was to evaluate risk factors for endoscopically proven peptic ulcer in chronic NSAID users.Methods: From 1989 to 2004, we consecutively selected the patients submitted for the first time to diagnostic upper digestive endoscopy by our endoscopy service and who took NSAIDs more than three times a month. The only exclusion criterion was when patients started NSAID therapy less than 3 weeks prior to the endoscopic examination. All patients were examined by a clinician prior to endoscopy to record clinical data.Results: The chronic NSAID user sample, 2,567 patients, comprised 1,476 (57.5%) females and 1,091 (42.5%) males (mean age: 58 years ± 15.5). In this population we found 184 (7.2%) duodenal ulcers and 142 (5.5%) gastric ulcers; only 16 (0.62%) patients had concomitant duodenal and a gastric ulcer. Helicobacter pylori positive patients amounted to 51.8%. The incidence of duodenal ulcer was 101 (9.3%) cases in males vs. 83 (5.6%) in females (p < 0.001), 58 (10.1%) in smokers vs. 124 (6.4%) in non-smokers (p < 0.003), and 105 (10.4%) in Helicobacter pylori positive subjects vs. 30 (3.3%) in Helicobacter pylori negative subjects (p < 0.001). Only age proved significantly predictive of gastric ulcer (57.4 vs. 67.4 yrs; p < 0.001). The consumption of PPIs was associated with the lowest prevalence of duodenal ulcer, 13 (4.3%) cases, while significantly higher values were found for antacids 13(6.7%), H2-antagonists 44 (10.8%), other antiulcer drugs 39 (7.6%) and no therapy 75 (6.5%) (p < 0.03). In the case of gastric ulcer this association was not significant (p = ns). Over the study period we observed a statistically significant decreasing incidence of duodenal ulcers (Spearman correlation p < 0.002) but not of gastric ulcer (p=ns)Logistic regression analysis identified male sex (OR 1.86, CI 95% 1.28-2.70; p < 0.001), smoking (OR 1.84; 1.25-2.73; p < 0.001), presence of Helicobacter pylori (OR 3.63; 2.37-5.58; p < 0.001) and emergency endoscopy (OR 6.04; 3.48-10.5; p < 0.001) as risk factors for duodenal ulcer, whereas only age (OR 1.04; CI 95% 1.03-1.06; p < 0.001) and emergency endoscopy (OR 4.66; 2.55-8.50; p < 0.001) were predictive of occurrence of gastric ulcer. Results: In chronic NSAID consumers, male sex, smoking and presence of Helicobacter pylori are important factors associated with an increased risk of developing duodenal ulcer, whereas only age emerged as a major risk factor for gastric ulcer. Treatment with proton pump inhibitors would appear to reduce the incidence of duodenal ulcer but not of gastric ulcer.