BACKGROUND : Despite significant technical and training improvements, the incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) has not significantly dropped. Although many studies have evaluated the efficacy of various agents, e.g. nonsteroidal anti-inflammatory drugs, octreotide, antioxidants, administered via various dosages, routes (oral, intrarectal or parenteral), and schedules (before or after the procedure), the results have been conflicting. OBJECTIVE : To evaluate efficacy of three pharmacologic prophylactic methods for prevention of PEP. METHODS : In this prospective, single-center randomized trial, patients who underwent first-time ERCP for choledocholithiasis were randomly assigned to three groups. The first group received 600 mg N-acetylcysteine 15 min prior to ERCP, and per-rectum administration of 50 mg indomethacin both prior to and after completion of the ERCP. The second group was administered only the 50 mg indomethacin per-rectum both prior to and after the ERCP. The third group was administered per-rectum 100 mg indomethacin only after the ERCP, representing the control group given the guideline-recommended regimen. The primary end-point was PEP prevention. RESULTS : Among the total 211 patients evaluated during the study, 186 fulfilled the inclusion criteria and completed the protocol. The percentages of patients who developed PEP in each of the three groups were not significantly different (χ2 = 2.793, P = 0.247). Among the acute PEP cases, for all groups, 14 patients developed mild pancreatitis (77.77%) and 4 moderate. No severe cases of PEP occurred, and in all PEP cases the resolution was favorable. No adverse events related to the medications (digestive hemorrhage, rectal irritation, or allergies) occurred. CONCLUSIONS : The efficacies of split-dose indomethacin and combined administration (N-acetylcysteine with indomethacin) for preventing PEP were similar to that of the standard regimen.