The Influence of Challenging Biliary Cannulation Resulting from Duodenal Papillary Lesions on the Outcomes and Complications Associated with Endoscopic Retrograde Cholangio-Pancreatography. Background: The major duodenal papillary (MDP) lesions make biliary cannulation more difficult which has a significant impact on achievement and hazards of ERCP in adults. We aimed to assess difficult biliary cannulation (DBC) due to MDP lesions and evaluate the success and potential complications during and after ERCP. Methods: A recruited 120 patients in a case control study who received ERCP for either diagnostic or therapeutic purposes and classified into 3 groups: Group A (N=40): Those with abnormal morphology of MDP (anatomical variant or pathological lesions) and DBC. Group B (N=40): patients with normal morphology of MDP and DBC. Group C (N=40): patients with type 1 and easy biliary cannulation as control group. All patients underwent detailed history, clinical evaluation, laboratory tests, radiological assessment and ERCP. Results: Overall successful biliary cannulation was achieved in 104/120 (86.67%) patients, while in the other 16/120 (13.33%) patients, biliary cannulation failed and post-ERCP complications' rate has been (18.33%), pancreatitis (10.8 %) and hemorrhage (7.5%). In addition, the potential independent factor predicting DBC was pancreatic mass, history of cholecystectomy, intra-diverticular papilla, the presence of the main duodenal papilla and/or biliary stenosis on imaging. However, the risk factors predicting PEP were the duration of cannulation, number of trials of cannulation, morphological variation of papilla and duodenum, the use of precut and sphincterotomy. Conclusion: Difficult biliary cannulation due to duodenal papillary lesions has an important effect on success and complications of ERCP.