Risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) complications have been extensively studied and are well established; most complications are mild and self-limiting. This study aims to identify patients at risk of severe early post-ERCP complications. We conducted a retrospective cohort study with data from 2810 ERCP procedures performed at Ghent University Hospital between 2016 and 2022. Patient records and a maintained ERCP registry were used to identify all ERCP-related complications and possible risk factors. The AGREE classification was used to determine the severity of the complication. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of severe complications. Out of 2810 procedures, 223 cases (7.9%) had post-ERCP complications, with severe complications occurring in 20.3% of cases. The most common severe complication was haemorrhage (22/49 severe complications, 44.9%), with perforation having the highest probability of being severe (10/15 cases, 67%). Independent predictors of severe complications included anticoagulative therapy (OR 6.3, 95% CI 1.4-28.3, = 0.016) and high procedural difficulty (Schutz category 3: OR 11.5, 95% CI 2.4-54.6, = 0.002; category 4: OR 5.9, 95% CI 1.4-23.5, = 0.012). Patients on anticoagulation and those undergoing complex ERCP procedures (Schutz 3 or 4) are at particular risk of severe procedure-related complications.