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Long-term aspirin use in cardiovascular disease prevention may result in gastrointestinal bleeding. Although proton pump inhibitors (PPI) have been shown to reduce the risks of peptic ulcers and dyspeptic symptoms in long-term aspirin users in the randomized controlled trials, there are safety concerns about the long-term use of PPI.What is the safety and efficacy of PPI in patients using aspirin in long term for prevention of cardiovascular diseases and stroke?We searched MEDLINE, EMBASE, CENTRAL, CINAHL, ProQuest, and relevant references from inception through February 2015, and used random-effects model for meta-analysis.A total of 10 publications from 9 studies (n = 6382) were included in the meta-analysis. Compared with control, PPI reduced the risks of peptic ulcers [risk ratio (RR): 0.19; 95% confidence interval: 0.13–0.26; P < 0.00001], gastric ulcers [0.24 (0.16–0.35); P < 0.00001], duodenal ulcers [0.12 (0.05–0.29); P < 0.00001], bleeding ulcers [0.22 (0.10–0.51); P = 0.0004], and erosive esophagitis [0.14 (0.07–0.28); P < 0.00001]. PPI increased the resolution of epigastric pain [1.13 (1.03–1.25); P = 0.01], heartburn [1.24 (1.18–1.31); P < 0.00001], and regurgitation [1.26 (1.13–1.40); P < 0.0001], but did not increase the risks of all-cause mortality [1.72 (0.61–4.87); P = 0.31], cardiovascular mortality [1.80 (0.59–5.44); P = 0.30], nonfatal myocardial infarction/ischemia [0.56 (0.22–1.41); P = 0.22], ischemic stroke/transient ischemic attack [1.09 (0.34–3.53); P = 0.89] and other adverse events.The PPI seems to be effective in preventing peptic ulcers and erosive esophagitis and in resolution of dyspeptic symptoms without increasing adverse events, cardiac risks or mortality in long-term aspirin users.