Peptic ulcer disease (PUD) has been described in the absence of Helicobacter pylori (Hp) infection, suggesting that different factors are involved in its etiopathogenesis. We investigated prevalence and characteristics of Hp-negative (Hp-) PUD in an area of Northern Italy and calculated the rate of Hp-positive (Hp+) patients with PUD in whom Hp might be coincidental and not causal. Four hundred nine consecutive patients with endoscopically diagnosed PUD were enrolled in seven hospitals. Hp infection was assessed by rapid urease test and histologic examination. The attributable risk percentages in different age groups were calculated by appropriate formulas. Of 409 patients, 31 (7.6%) were Hp- (gastric, 8.3%; duodenal, 7.6%). Age, nonsteroidal antiinflammatory drug (NSAID) consumption, and complication rates were significantly higher in Hp-than Hp+ patients with duodenal ulcers (DUs). Of the Hp-patients with DU, 58% did not use NSAIDs. In patients with Hp+ DU, the attributable risk percentage for Hp infection in patients aged <40 years, 40-60 years, or >60 years was 98%, 88%, and 66%, respectively. The prevalence of Hp- PUD was about 8%, mainly unrelated to any known etiologic factor. In about one-third of Hp+ patients with PUD aged over 60 years, Hp infection might be coincidental and not causal.