Background: Common bile duct stones (CBDS) represent a widespread problem, and the commonly used approach for this issue is endoscopic retrograde cholangiopancreatography (ERCP). Nevertheless, the difficult biliary cannulation (DBC) throughout ERCP for biliary duct stones continues to pose a considerable obstacle, hence elevating the likelihood of post-ERCP pancreatitis (PEP) and other unfavorable occurrences. This study aimed to recognize pre-procedural aspects that can expect DBC during ERCP for CBDS, thereby facilitating appropriate preventive measures and optimizing patient outcomes.

Methods: This prospective cohort study involved 100 participants aged ≥ 18 years with CBDS undergoing ERCP. DBC is failing to access the papilla after five attempts, spending over five minutes attempting cannulation after initially contacting the papilla, and encountering unwanted cannulation or opacification of the pancreatic duct on more than one occasion.

Results: DBC was present in 43% of the patients. Distal biliary stricture (odds ratio (OR) 4.33, p=0.012), interdiverticular papilla (OR 6.27, p=0.027), attempted stone removal (OR 6.13, p=0.018), precut sphincterotomy (OR 11.121, p=0.036), prophylactic pancreatic stent placement (OR 10.645, p=0.005), AST (OR 0.903, p=0.003), direct bilirubin (OR 288.94, p=0.006), uric acid (OR 1.557, p=0.031), C-reactive protein (OR 2.268, p<0.001), triglycerides (OR 1.034, p<0.001), and glucose (OR 1.120, p<0.001) were independent predictors for DBC.

Conclusions: The incidence of DBC in patients was 43%. Several factors that could predict DBC during ERCP for CBDS patients, including anatomical, procedural, and biochemical parameters.