Background: Pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP), is termed post-ERCP pancreatitis (PEP). It is a common complication and can be associated with substantial morbidity. Pharmacoprophylaxis using several agents yielded inconclusive results. Indomethacin can ameliorate pancreatitis because of its anti–inflammatory properties. Aim: Evaluating the protective effect of indomethacin on PEP Methods: During 36 months a prospective randomized double blind study over 80 patients deemed eligible for ERCP who received either oral indomethacin or placebo. Incidence and severity of PEP were the main endpoints observed. In addition recording of serum pancreatic enzyme levels at consequent intervals, duration of hospitalization and pain medication requirements were done. The suffered adverse effects Results: There was no difference between the two study groups as regards demographics, risk factors for post-ERCP pancreatitis or baseline pancreatic enzyme levels. The indomethacin group showed significantly lower serum amylase levels than the control group at 24 hrs [360 vs 437 U/L (p < 0.01)] and significantly lower levels of serum lipase at 24 hrs & 72 hrs when compared to control group [324 vs 512 U/L (p < 0.01) & 257 vs 327 U/L (p = 0.04) respectively]. The indomethacin group had fewer episodes of post-ERCP pancreatitis in comparison to the control group [5% vs 17.5% (p = 0.04)], which meant a lower incidence rate of this complication (NNT = 8). Also, pancreatitis episodes in the indomethacin arm were less in severity [0/2 vs 4/7 (p = 0.02)]. Further analysis showed that patients in the indomethacin group required shorter hospitalization [1.3 days vs 8.7 days (p < 0.01)]. There was no difference between the study groups as regards the complication of the procedure or the expected adverse effects of the investigated medication. Conclusion: Indomethacin had a significant role in decreasing the incidence of post-ERCP pancreatitis and reducing its severity.