Objective To perform a systematic review on the safety (i.g. cardiovascular, mortality and gastrointestinal bleeding) of clopidogrel versus clopidogrel combined with proton pump inhibitors (PPIs) for the patients with coronary heart disease. Methods Such databases as The Cochrane Library, PubMed, EMbase, SSCI, VIP, CNKI, and CBM were searched from the date of their establishment to September 2010. The bibliographies of the retrieved articles were also checked. The data was extracted and evaluated by two reviewers independently. The RevMan 5.0 software was used for meta-analyses. Results A total of 29 studies were included. The results of meta-analyses showed that the use of clopidogrel combined with PPIs was associated with increasing the risk of cardiovascular events (RR=1.27, 95%CI 1.09 to 1.47), as well as myocardial infarction (RR=1.45, 95% CI 1.20 to 1.76), total mortality (RR=1.23, 95%CI 1.06 to 1.43), and rethrombosis (RR=1.37, 95%CI 1.01 to 1.86). However, there was no enough evidence to reach the conclusion that the combination use could benefit the situation of gastrointestinal bleeding (RR=0.84, 95%CI 0.47 to 1.50). Conclusion?Compared with clopidogrel, the combination use of clopidogrel and PPIs increases cardiovascular events, mortality, and the risks of myocardial infarction and rethrombosis. However, more clinical studies are required to assess the effect of reducing gastrointestinal bleeding.