Objective?To assess the effectiveness and safety of diclofenac, one of the routine-used NSAIDs, in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). Methods Firstly, the electronic searches were conducted to retrieve Randomized controlled trials (RCTs) from The Cochrane Library, PubMed, Embase, OVID, CBM, CNKI, VIP and WanFang Data. Secondly, 12 kinds of specific Chinese journals like Chinese Journal of Gastroenterology and conference proceedings were hand-searched till June 2011, and all references in all included trials were searched, too. The RCTs on diclofenac for preventing PEP were identified and retrieved. The systematic review was conducted by using methods and principles recommended by the Cochrane Collaboration. Results A total of 5 RCTs involving 675 PEP patients were included. The Meta-analysis showed that diclofenac might reduce the incidence of PEP (OR=0.41, 95%CI 0.18 to 0.95, P=0.04), but the sensitivity analysis indicated this result was not stable. No evidence showed diclofenac could reduce the incidence of severe PEP (OR=0.40, 95%CI 0.08 to 2.06, P=0.27). And no adverse reactions related to the drug were reported. Conclusion Diclofenac may be safe and effective in reducing the incidence of PEP, but it has no significant effect on preventing severe PEP. Considering the methodological and scale limitation of included studies, this conclusion still needs to be proved by more large-scale and high-quality RCTs.