Background and Aims: Certain appearances of the major duodenal papilla have been claimed to make cannulation more difficult during ERCP. This study uses a validated classification of the endoscopic appearance of the major duodenal papilla to determine if certain types of papilla predisposes to difficult cannulation. Methods: Patients, with a naïve papilla, scheduled for ERCP, were included. The papilla was classified into one of 4 papilla types before cannulation started. Time to successful bile duct cannulation, attempts and number of pancreatic duct passages were recorded. Difficult cannulation was defined as, after 5 minutes, 5 attempts, or 2 pancreatic guide-wire passages. Results: One thousand four hundred one patients were included from 9 different centers in the Nordic countries. The overall frequency of difficult cannulation was 42% (95% CI, 39%-44%). Type 2, small papilla, (52%; 95% CI, 45%-59%) and Type 3 protruding or pendulous papilla (48%; 95% CI, 42%-53%) were more frequently difficult to cannulate compared with Type 1, regular papilla (36%; 95% CI, 33%-40%, both p<0.001). If an inexperienced endoscopist started cannulation, the frequency of failed cannulation increased from 1.9% to 6.3% (p<0.0001), even though they were replaced by a senior endoscopist after 5 minutes. Conclusion: The endoscopic appearance of the major duodenal papilla influences bile duct cannulation. Small, Type 2, and protruding or pendulous Type 3 papillae are more frequently