Background and aim <p>Difficult biliary cannulation (DBC) prolongs endoscopic retrograde cholangiopancreatography (ERCP) manipulation and increases post-ERCP complications. Several cannulation techniques, including guidewire and cutting-based methods, have been proposed to facilitate the procedure; however, the optimum choice among these approaches remains inconclusive. We conducted a network meta-analysis to compare the techniques for DBC.</p> Methods <p>Three major bibliographic databases were reviewed for enrollment of comparative trials which took place prior to January 23, 2024. We included adults diagnosed with DBC and compared two or more of seven possible interventions, including controlled group, precut papillotomy (PP), precut fistulotomy (PF), delayed precut papillotomy (dPP), delayed precut fistulotomy (dPF), transpancreatic biliary sphincterotomy (TPS), and the double-guidewire technique (DGW). Our focus was on the deep cannulation rate and any post-ERCP complications, including pancreatitis, bleeding, perforation and infection which may have occurred during the follow-up periods.</p> Results <p>Seventeen randomised controlled trials involving a total of 2,189 participants were used in the analyses. When compared with the control group, TPS was shown to be significantly superior to the other techniques in cannulation efficacy (OR 6.00, 95% CI: 1.29 ~ 27.96), while only PF was found to be significantly associated with a lower complication rate (OR 0.61, 95% CI: 0.40 ~ 0.93). Subgroup analysis also found that patients receiving PF experienced significantly less post-ERCP pancreatitis in comparison to the control group, with no differences in being seen in bleeding, perforation or infection after ERCP.</p> Conclusions <p>For DBC patients, only TPS achieved better cannulation efficacy, while PF showed a lower complication rate with statistical significance, particularly in post-ERCP pancreatitis.</p>