Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Rectal Indomethacin and prophylactic pancreatic stent placement have been shown to be effective for the prevention of post-ERCP pancreatitis. However, there remains considerable controversy regarding the usefulness of protease inhibitors (PIs) in preventing PEP. This systematic review of randomized controlled trials (RCTs) aims to compare PIs with other pharmacological agents and/or placebo. CENTRAL (the Cochrane library), MEDLINE, EMBASE, and CINAHL databases, and major conference proceedings from DDW, UEGW and ACG up to July 2017 were searched for RCTs examining PIs against other pharmacological agents and/or placebo. Study selection, data extraction and quality assessment were conducted independently by two authors. The primary outcome was PEP. Secondary outcomes included severity of PEP and other ERCP-related complications such as bleeding, perforation, cholangitis, cholecystitis and mortality. The outcomes were pooled into a meta-analysis using risk ratios (RR) with 95% confidence intervals (CI; Mandel-Haenszel method; random effects model). Heterogeneity was assessed by Chi2 test (P<0.15) and I2 test (> 25%). The risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. 23 RCTs (7091 patients) comparing four different types of PIs with placebo were included in this review. Overall, there was a significant reduction in the risk of post-ERCP pancreatitis with PIs compared with placebo (RR 0.56, 95% CI 0.44–0.73, I2 = 33%). Among the seven studies that compared Ulinastatin with placebo, the incidence of PEP was 3.9% in the PI group vs. 8.3% in the placebo group (RR 0.48; 95% CI 0.30–0.76; I2 = 0%). Among the seven studies that compared Nafamostat with placebo, the incidence of PEP was 3.8% in the PI group vs. 8.2% in the control group (RR 0.43; 95% CI 0.31–0.59, I2=0%). There was no statistically significant difference found in the comparison between Gabexate versus placebo (RR 0.68; 95% CI 0.41–1.12; I2 = 48%). In the one study that assessed Aprotinin versus placebo, there was no statistically significant difference (RR 1.38, 95% CI 0.66–2.86). Overall, the risks of bleeding (1.5%), perforation (0.2%), cholangitis (1.2%) and mortality (0.3%) appeared to be low. Protease inhibitors, specifically Nafamostat and Ulinastatin, are effective in preventing PEP. Further studies are needed to assess the optimal dose, timing and duration of PI, as well as the cost-effectiveness in different subgroups of patients. As well, the role of PIs along with prophylactic PD stent placement and rectal NSAIDs will need to be further elucidated in RCTs. Post-ERCP Pancreatitis in PIs versus Placebo None