INTRODUCTION: Post-ERCP acute pancreatitis (post-ERCP-AP) occurs in ∼5% of patients undergoing ERCP, severe in ∼1%. Despite multiple trials, optimal prophylaxis remains undetermined. We sought to clarify the effectiveness of prophylactic interventions for post-ERCP AP through multiple meta-analyses of randomised controlled trials (RCTs). METHODS: MEDLINE, EMBASE and the Cochrane Library were searched by two independent reviewers to identify all RCTs that tested treatments to reduce post-ERCP AP. Data were extracted to permit Jadad scoring, grouping of RCTs by therapeutic mechanism and separate meta-analysis of each group. The main outcome measure was post-ERCP AP, defined as amylase elevated to >3× upper limit of normal with >24 h abdominal pain. RESULTS: 71 RCTs of the highest quality (Jadad score 5 for pharmacological and three for interventional trials) were identified. Pancreatic stents (trials (T)—5; patients (P)—377; RR 0.20; 95% CI 0.09 to 0.42) were most effective; significant reductions in post-ERCP AP resulted from secretion inhibitors (T—12; P—4851; RR 0.54; CI 0.36 to 0.83), protease inhibitors (T—9; P—3752; RR 0.54; CI 0.38 to 0.78) and smooth muscle relaxants (T—9; P—2110; RR 0.67; CI 0.52 to 0.87). Non-steroidal anti-inflammatory drugs (NSAIDs; T—4; P—733; RR 0.68; CI 0.46 to 1.00), interleukin-10 (IL-10; T—3; P—642; RR 0.79; CI 0.55 to 1.14), anti-oxidants (T—5; P—2100; RR 0.90; CI 0.54 to 1.50), anti-coagulants (T—2; P—533; RR 0.85; CI 0.48 to 1.53), non-ionic (vs ionic) contrast agents (T—8; P—3095; RR 1.32; CI 0.92 to 1.88), wire guided cannulation, (T—7; P—2103; RR 0.63; CI 0.34 to 1.17) pre cut papillotomy (T—4; P—558; RR 0.57; CI 0.20 to 1.59) and steroids (T—3; P—924; RR 1.09; CI 0.70 to 1.70) did not reduce post-ERCP AP. CONCLUSION: This is the most comprehensive systematic review on the subject to date which shows that pancreatic stents, secretion and protease inhibitors and smooth muscle relaxants reduce the risk of post-ERCP AP. Large well-designed RCTs of combination vs single agent prophylaxis are required. COMPETING INTERESTS: None declared.