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Postendoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis (PEP) is the most common complication following ERCP. We carried out a systematic review and meta-analysis of the global literature on PEP prevention to provide clinical guidance and a framework for future research in this important field.PubMed, Embase, Science Citation Index, Ovid, and the Cochrane Controlled Trials Register were searched by two independent reviewers to identify full-length, prospective, randomized controlled trials (RCTs) published up until March 2016 investigating the use of pancreatic duct stents and pharmacological agents to prevent PEP.Twelve RCTs comparing the risk of PEP after pancreatic duct stent placement (1369 patients) and 30 RCTs comparing pharmacological agents over placebo (10251 patients) fulfilled the inclusion criteria and were selected for final review and analysis. Meta-analysis showed that prophylactic pancreatic stents significantly decreased the odds of post-ERCP pancreatitis [odds ratio (OR), 0.28; 95% confidence interval (CI), 0.18–0.42]. Significant OR reduction of PEP was also observed in relation to rectal administration of diclofenac (OR, 0.24; 95% CI, 0.12–0.48) and rectal administration of indometacin (OR, 0.59; 95% CI, 0.44–0.79) compared with placebo. Subgroup analysis showed a significant reduction with bolus-administered somatostatin (OR, 0.23; 95% CI, 0.11–0.49). Subgroup analysis showed a significant reduction with bolus-administered somatostatin (OR, 0.23; 95% CI, 0.11–0.49).Pancreatic stent placement, rectal diclofenac, and bolus administration of somatostatin appear to be most effective in preventing post-ERCP pancreatitis.