Introduction: Endoscopic retrograde cholangiopancreatography (ERCP) is fundamental for treatment of pancreatico-biliary diseases, but results in PEP in up to 15% of patients. Phospholipase A2 (PLA2) is an important factor in the pancreatitis inflammatory cascade and NSAIDs, which inhibit PLA2 activity, prevent PEP in high-risk patients. We endeavored to identify and quantitatively synthesize the existing high-quality data to date on rectal NSAID use for the prevention of post ERCP pancreatitis in unselected patients without specific risk factors for PEP. Methods: In collaboration with a librarian, we searched the following databases: Ovid Medline (coverage 1946 – Present), Embase and Embase Classic (coverage 1947 – Present), Cochrane Library (coverage 1898-present), Web of Science (coverage 1900-present), Clinicaltrials.gov, and Google Scholar through April 2021. Using the Covidence system, two independent reviewers identified randomized controlled studies assessing rectal NSAIDs for PEP prevention in unselected patients. Our primary outcome was odds of developing PEP and our secondary outcome was odds of developing moderately severe or severe PEP. Pooled odds ratios were estimated using the random effects model. Results: After review of 504 abstracts and 234 full text documents, we identified 25 randomized controlled trials evaluating rectal NSAIDs for the prevention of PEP in unselected patients; 4071 patients received rectal NSAIDs and 4005 patients received a placebo. The most frequent NSAID used was diclofenac in 56% of studies, followed by indomethacin in 36%, ketoprofen in 4%, and naproxen in 4%. Unselected patients receiving rectal NSAIDs were less likely to develop PEP (OR 0.59, 95% CI 0.45-0.78) (Figure 1) as well as moderately severe and severe pancreatitis (OR 0.50, 95% CI 0.33-0.75). Conclusion: In unselected patients undergoing ERCP, rectal NSAID administration decreases the risk of post-ERCP pancreatitis and development of moderately severe or severe PEP. They should be considered for unselected patients undergoing ERCP, not simply those high risk for PEP.Figure 1.: Baseline characteristics and clinical outcomes in patients who has ERCP with glucagon (ERCP w glucagon, group 1) compared to individuals ERCP without glucagon (ERCP wo glucagon, group 2) Note: SD-Standard Deviation; € A 1:1 propensity score matching was done based on the following variables: age, gender, race, hypertension, diabetes mellitus, obesity, chronic kidney disease (CKD), Ischemic heart diseases (IHD), chronic obstructive pulmonary disease, indomethacin use, sphincter of Oddi dysfunction (SOD).