The relation between H pylori infection and use of non-steroidal anti-inflammatory drugs (NSAIDs) in the pathogenesis of peptic-ulcer disease is controversial. We undertook a meta-analysis to address this issue. By computer and manually we sought observational studies on the prevalence of peptic-ulcer disease in adult NSAID takers or the prevalence of H pylori infection and NSAID use in patients with peptic-ulcer bleeding. Summary odds ratios were calculated from the raw data. Tests for homogeneity were done. Of 463 citations identified, 25 studies met inclusion criteria. In 16 studies of 1625 NSAID takers, uncomplicated peptic-ulcer disease was significantly more common in patients positive than in those negative for H pylori (341/817 [41.7%] vs 209/808 [25.9%]; odds ratio 2.12 [95% CI 1.68-2.67]). In five controlled studies, peptic-ulcer disease was significantly more common in NSAID takers (138/385 [35.8%]) than in controls (23/276 [8.3%]), irrespective of H pylori infection. Compared with H pylori negative individuals not taking NSAIDs, the risk of ulcer in H pylori infected NSAID takers was 61.1 (9.98-373). H pylori infection increased the risk of peptic-ulcer disease in NSAID takers 3.53-fold in addition to the risk associated with NSAID use (odds ratio 19.4). Similarly, in the presence of risk of peptic-ulcer disease associated with H pylori infection (18.1), use of NSAIDs increased the risk of peptic-ulcer disease 3.55-fold. H pylori infection and NSAID use increased the risk of ulcer bleeding 1.79-fold and 4.85-fold, respectively. However, the risk of ulcer bleeding increased to 6.13 when both factors were present. Both H pylori infection and NSAID use independently and significantly increase the risk of peptic ulcer and ulcer bleeding. There is synergism for the development of peptic ulcer and ulcer bleeding between H pylori infection and NSAID use. Peptic-ulcer disease is rare in H pylori negative non-NSAID takers.