BACKGROUND: Endoscopic retrograde cholangiopancreatography is a widely used therapeutic modality for the pancreaticobiliary tree. However, it is responsible for the highest rates of complications among the endoscopic procedures, especially post-endoscopic retrograde cholangiopancreatography pancreatitis. The preventive methods include mechanical and pharmacological approaches, such as the use of non-steroidal anti-inflammatory drugs. OBJECTIVE: To compare the efficacy of two different strategies using non-steroidal anti-inflammatory drugs for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis, and to clarify the uncertainty about the route of administration of non-steroidal anti-inflammatory drugs in the prevention of this complication. METHODS: This was a prospective trial. Two therapeutic groups were compared with a control group that was composed of patients who underwent endoscopic retrograde cholangiopancreatography, performed in the same service and by the same team in the period preceding the study (historical series), without the administration of any type of prophylaxis. The first group received 100 mg rectal diclofenac. The second group received 100 mg intravenous ketoprofen. Both groups were compared, separately and jointly, with the control group. RESULTS: Post-endoscopic retrograde cholangiopancreatography pancreatitis occurred in 4.39% (12/273) of the participants. In the group without prophylaxis, the incidence was 6.89% (10/145). Among those who received intravenous ketoprofen, the incidence was 2.56% (2/78). No cases of acute post-procedural pancreatitis were observed in the group that received rectal diclofenac (0/52). Although there was no statistical difference between the therapeutic groups when they were separately analyzed, a statistical difference in the prevention of post-procedural pancreatitis was observed when they were analyzed together (P=0.037). CONCLUSION: This study provides evidence for the efficacy of non-steroidal anti-inflammatory drugs in the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis.