Aim: The main complication of Endoscopic retrograde cholangiopancreatography (ERCP) is post-ERCP pancreatitis (PEP)., Background: Based on demographic characteristics and underlying issues and ERCP indication, patients are categorized as high risk or low risk. There have been no studies on the synergistic effects of NSAIDS and hydration therapy, separately sorted by the risk assessment of PEP in different groups of patients., Methods: This study included 281 eligible participants after exclusion. According to demographic characteristics and co-morbidities, the patients were divided to high risk and low risk. The high-risk group was divided randomly into two subgroups and both of them received NSAIDs (100 mg rectal Diclofenac). One group received standard hydration (1.5mg/kg/hr), another the other received aggressive hydration (3mg/kg/h). The low-risk group received standard hydration. One of its subgroups received NSAIDs, while others did not. The efficacy of these preventions was compared across 4 subgroups., Results: The mean age was 59.85±17.17. Eight hours after ERCP, the amylase and lipase were significantly higher in the high-risk group with standard hydration (P=0.00). Amylase, lipase 8 hours, between two low risk subgroups, NSAIDs had no significant effect (P=0.38, P=0.95, respectively). After adjustment based on cannulation, manipulation and duration of time, the results had no change (P=0.64, P=0.19, P=0.61)., Conclusion: The aggressive hydration could significantly decrease the risk of PEP. However, the low-risk group was exposed to the lowest risk of PEP. NSAIDs could not help to decrease the rate PEP in the low-risk groups alone. Overall, it seems hydration and NSAIDs therapy had synergistic outcome in high-risk patients., (©2020 RIGLD, Research Institute for Gastroenterology and Liver Diseases.)