OBJECTIVES: Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is used to diagnose and treat of pancreatico-biliary disorders. Post ERCP pancreatitis (PEP) is one of the life threatening complications. This trial performed to assess the effect of indomethacin versus somatostatin for prevention of PEPMETHODS: All 101 adult patients who referred for ERCP were enrolled in this trial. Patients randomly assigned in group A (N=51) who received indomethacin (100 mg) rectally immediately before ERCP beginning and group B (N=50) who received an intravenous injection of somatostatin (250 bolus injection + 500 infusion =750 mcg) during 2 hours. Demographic data, ERCP recording data/ findings, PEP rate, severity of PEP and drug adverse effects were recorded before and during the first day after ERCP. RESULTS: Totally 90 patients (55.6% male) with the mean age of 61.64 ± 18.89 years completed the study. There was no statistically significant difference between the two treatment groups in respect of demographic characteristics, laboratory, clinical and ERCP data. The rate of PEP, severity of PEP, ICU admission rate, hospital stay and mortality rate were not significantly different between treatment groups (P= 0.830, P>0.999, P>0.999, P=0.511, P>0.999 respectively). No serious adverse effects were reported in this study. CONCLUSION: There was no significant difference between treatment modalities regarding in the PEP rate, the severity of PEP, hospital staying, ICU admission rate, and mortality rate. Somatostatin may be a safe and tolerable substitute for patients who are not a good candidate for NSAIDs administration