Recently, dupA was reported as a new virulence factor in Helicobacter pylori, but its association with gastroduodenal disorders and its mode of action are still unclear. Here, an association of the dupA status with different disease groups was determined and a biological explanation for the observed associations was tested. In total, 216 H. pylori isolates were obtained from 232 presumed H. pylori-infected patients. A positive association was observed between the occurrence of duodenal ulcer (DU) and the presence of dupA [odds ratio (OR) 24.2; 95 % confidence interval (CI) 10.6-54.8]. In addition, an inverse association between the occurrence of gastric cancer (GC) [OR 0.16; 95 % CI 0.05-0.47] and gastric ulcer (GU) [OR 0.34; 95 % CI 0.16-0.68] with the presence of dupA was observed. A putative explanation for the observed associations might be a more corpus-located infection (pan-gastritis) by the dupA-positive strains due to their increased acid resistance. Indeed, a strong association between dupA-positive H. pylori isolated from gastritis patients and in vitro acid resistance was observed (P<0.05). The observed higher acid resistance of the dupA-positive strains suggests that these strains are adapted to a stomach with high gastric acid output. This may in part explain the observed associations, as an increased gastric acid output is thought to be typical for an antrum-predominant H. pylori infection and, whilst this is associated with an increased risk of DU formation, it also decreases the risk for the genesis of GUs and GC.