We investigated and compared 2 clinical strategies to prevent postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).We retrospectively reviewed data from patients who underwent ERCP between 2008 and 2014. Of 623 patients at high risk for PEP, 145 were treated with prophylactic pancreatic stent placement (PSP) only, and 478 were treated with rectal indomethacin (RI) only, for PEP prevention. Patients were matched by one-to-one propensity score matching (PSM) by risk factors, with overall PEP incidence as primary outcome, and moderate or severe PEP and complication rates as secondary outcomes.Of 623 patients with high-risk factors, 145 pairs were generated after PSM. Thirty-two patients developed pancreatitis-10 (6.9 %) in the PSP group and 22 (15.2 %) in the RI group (P = 0.025). Moderate-to-severe pancreatitis developed in 5 patients (2.8%) in the PSP group and 14 patients (9.7 %) in the RI group (P = 0.047).Although indomethacin represents an easy, inexpensive treatment, prophylactic PSP is still the better prevention strategy for PEP.