Post-ERCP pancreatitis (PEP) is a common complication most feared by endoscopists. Incidence ranges widelly from 2.1% to 24.4%, which results from patient heterogeneity and differences in endoscopist expertise, method, PEP definition, and severity. Pathophysiology is multifactorial, and involves a combination of chemical, thermal, mechanical, hydrostatic, enzymatic, allergic, and microbiological factors resulting from papillary instrumentation and/or contrast administration within the pancreatic duct (volume and osmolarity). Even genetic abnormalities may represent a risk factor, as is the case with homozygous alpha-1-antitrypsin deficiency, which leads to an increase in hemorrhagic PEP rates.