There are two lines of thought regarding the interrelationship between the damaging effects of Helicobacter pylori and those of nonsteroidal anti-inflammatory drugs (NSAIDs) on the gastroduodenal mucosa. First, both pathogenic factors exert a damaging effect on the mucosa, and therefore an additive, or even synergistic, effect occurs, leading to aggravation of mucosal damage. Second, mutual antagonism exists, leading to one of the pathogenic factors actually deriving some protection from the damaging potential of the other. Microscopically, H. pylori– and NSAID-associated gastritis are recognized as two separate entities. Furthermore, pathologically, the mechanisms of mucosal damage of the two factors have important differences; for example, H. pylori increases the synthesis of prostaglandins, whereas NSAIDs inhibit prostaglandin synthesis. The role of H. pylori infection in patients with NSAID-associated peptic ulcers has been addressed recently in two large, randomized, multicenter trials. From these studies, it appears that antisecretory drugs are more effective in H. pylori–positive peptic ulcer patients taking NSAIDs than in H. pylori–negative patients taking these drugs. The studies, however, do not provide any evidence that H. pylori infection reduces the pathogenic effects of NSAIDs. Other studies, however, have shown protection against NSAID-associated gastroduodenal damage in H. pylori–negative patients. Thus, there are no firm conclusions on the role of H. pylori infection in patients with NSAID-associated peptic ulcers. Based on the available data, however, practical considerations and guidelines are listed.