Helicobacter pylori and nonsteroidal antiinflammatory drugs independently cause gastroduodenal mucosal injury but the relationship between them remains unclear. We have performed a double-blind, parallel-group, placebo-controlled prospective study in 77 healthy volunteers aged 19-35 years who were randomly allocated to indomethacin (N = 15), one of three oxicams (piroxicam, chlortenoxicam, or CHF 1194; N = 36), or placebo (N = 26). Esophagogastroduodenoscopy was performed before and after four weeks of treatment and the mucosal appearances graded. Colonization with H. pylori was established at each endoscopy and gastrointestinal symptoms ware assessed by daily diary card. Seven subjects (9%) were positive for H. pylori before treatment (one placebo, one indomethacin, and five an oxicam); their H. pylori status remained unchanged. Two of 70 H. pylori-negative subjects became H. pylori-positive (2.9%), both of whom had received placebo. The endoscopic score deteriorated in 1/6 drug-treated H. pylori-positive subjects and in 0/1 taking placebo. Of the H. pylori-negative subjects whose endoscopic score deteriorated, three (13%) were taking placebo, four (28.6%) indomethacin, and eight (25.8%) an oxicam. Upper gastrointestinal symptoms were reported in eight (30.8%) of the subjects taking placebo (one subject negative for H. pylori became positive), eight (53.3%) indomethacin (one H. pylori-positive), and 10 (27.8%) an oxicam (one H. pylori-positive). There were no statistically significant differences between the H. pylori-negative and H. pylori-positive groups whether on drug or placebo. These findings suggest that H. pylori infection, at least in the short term, neither influences the propensity of nonsteroidal antiinflammatory drugs to produce macroscopic gastroduodenal mucosal injury nor does it effect the occurrence of upper gastrointestinal symptoms.