Background The type of major duodenal papilla could be associated with difficult biliary cannulation at first endoscopic retrograde cholangiopancreatography (ERCP) in adults. Methods This retrospective cross-sectional study included patients undergoing ERCP for the first time by an expert endoscopist. We defined the type of papilla according to the endoscopic classification of Haraldsson in type 1-4. The outcome of interest was difficult biliary cannulation, defined according to the European Society of Gastroenterology. To assess the association of interest, we calculated crude and adjusted prevalence ratios (PRc and PRa, respectively) and their respective 95% confidence intervals (CI) using Poisson regression with robust variance models, employing bootstrap methods. For the adjusted model we included the variables age, sex, and indication for ERCP, according to an epidemiological approach. Results We included 230 patients. The most frequent type of papilla was type 1 (43.5%), and 101 (43.9%) of the patients presented difficult biliary cannulation. The results were consistent between the crude and adjusted analyses. After adjusting for age, sex, and ERCP indication, the prevalence of difficult biliary cannulation was highest in patients with papilla type 3 (PRa 3.66, 95%CI 2.49-5.84), followed by patients with papilla type 4 (PRa 3.21, 95%CI 1.82-5.75), and patients with papilla type 2 (PRa 1.95, 95%CI 1.15-3.20) compared to patients with papilla type 1. Conclusion In adults undergoing ERCP for the first time, patients with papilla type 3 had a greater prevalence of difficult biliary cannulation than patients with papilla type 1.