Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs) are the two most important causal factors in gastroduodenal ulcer disease. The coincidence of both occurs frequently and, therefore, demonstration of a possible relationship, and the consequent attitude (giving or not eradication therapy) would have important implications. The lower H. pylori prevalence in gastric ulcer, in comparison with duodenal ulcer, seems to be due greatly to NSAIDs intake, although in a low number of patients this ulcer is not explained by either of these factors. Therefore, the finding of a gastroduodenal ulcer in an H. pylori-negative patient should suggest other possible causes, and among them NSAIDs outstands. Histologic gastritis found in a patient with NSAIDs intake is related to the subjacent presence of H. pylori and not with NSAIDs. It is not clear whether, in patients taking NSAIDs, the infection favors the appearance of dyspeptic symptoms. The possibility of H. pylori and NSAIDs having a synergistic effect on gastroduodenal ulcer disease is a debatable issue. H. pylori eradication in patients taking NSAIDs does not confer a clear advantage in ulcer healing, and the possible protecting effect of eradication on the development of an ulcer in subjects taking NSAIDs is doubtful. In an H. pylori-positive patient in whom an ulcer occurs while taking NSAIDs, it is not possible to know for sure whether the ulcer has been caused by the organism, by NSAIDs, or by both, and therefore it seems logical to administrate an eradication therapy. However, H. pylori eradication with the intention of preventing appearance of gastroduodenal lesions is not so evident. Finally, indications of traditional preventive treatment (with antisecretory drugs or mysoprostol) should not be influenced by the concomitant administration of H. pylori eradication therapy.