AIM: To investigate the association between use of nonsteroidal anti-inflammatory drugs (NSAID) and Helicobacter pylori infection, interactive effect of H. pylori infection and NSAID use on the development of peptic ulcer disease (PUD), and the effect of H. pylori eradication therapy on PUD development. MATERIAL AND METHODS: We performed a systematic literature search in EMBASE and PubMed for relevant articles published in English between January 1989 and August 2010, with the following MeSH and/or key words: non-steroidal anti-inflammatory drugs, or NSAIDs, Helicobacter pylori, or H. pylori, peptic ulcer disease or PUD, and randomized-control study or clinical trial. The meta-analysis was conducted using the Review Manager 4.2.2. RESULTS: In the analysis of five studies, the pooled prevalence of H. pylori infection was 74.5% and 71.1% in NSAID users and non-NSAID users, respectively, (OR = 0.65; 95% CI: 0.35-1.20, p = .170). In the analysis of nine studies, the pooled prevalence of PUD in NSAID users was 31.2% and 17.9% in the presence and absence of H. pylori infection, respectively, (OR = 3.08; 95% CI: 1.26-7.55, p = .010). Moreover, in the analysis of seven studies, PUD developed in 6.4% and 11.8% of NSAID users with and without eradication therapy, respectively (OR = 0.50; 95% CI: 0.36-0.74, p < .001). The preventive effect of the eradication therapy was further revealed in NSAID-naive users (OR = 0.26; 95% CI: 0.14-0.49, p < .0001) and in the Asian population (OR = 0.30; 95% CI: 0.16-0.56, p < .001). CONCLUSION: NSAID use is not associated with H. pylori infection in patients with PUD. PUD is more common in H. pylori positive than in negative NSAID users. Moreover, H. pylori eradication therapy reduces PUD incidence in NSAID users, especially in naive users and in the Asian population.