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Objective: To determine efficacy of diclofenac suppository in reducing post-ERCP pancreatitis (PEP) and identify risk factors for PEP. Methods: This is a placebo-based prospective study at Department of Medicine & Gastroenterology, Services Institute of Medical Sciences / Services Hospital, Lahore performed from January 2018 to June 2019. Patients were randomized to receive diclofenac suppository or glycerine suppository before ERCP. Both groups were compared for PEP using chi square x2 test while risk factors for PEP were determined using binary logistic regression. Results: Total of 165 patients with mean age 49.1(±15.2) and male to female ratio 1/1.6 (63/102) were included. Among 82 (49.7%) patients in diclofenac group, 8 (9.7%) developed pancreatitis while 19(22.9%) of 83(50.3%) in placebo group had PEP (p value 0.02). After multivariate analysis, age>45 years (p value 0.014, OR 3.2), Bilirubin >3 mg/dl (p value 0.004 OR 3.58), time to cannulation> 5 minutes (p value<0.000 OR 9.2), use of precut (p value< 0.000 OR 4.9), pancreatic duct cannulation (p value 0.000 OR 5.46) and total procedure time >30 minutes (p value 0.01 OR 3.92) were risk factors for PEP. Conclusion: Pre-procedure Diclofenac suppository reduces post-ERCP pancreatitis. Age > 45 years, serum bilirubin > 3 mg/dl, cannulation time > 5 minutes, use of precut, pancreatic duct cannulation and procedure time > 30 minutes are risk factors for post-ERCP pancreatitis. [ABSTRACT FROM AUTHOR]