Acute necrotizing pancreatitis (ANP) is an uncommon but serious complication of endoscopic retrograde cholangiopancreatography (ERCP). This study compares the severity, clinical course, and long-term outcome of ERCP-induced ANP with ANP induced by other causes. A review of 72 consecutive patients with ANP treated surgically at the Mayo Clinic identified ERCP as the cause in 6 patients (8%). Compared to the remaining 66 patients, the post-ERCP group had higher APACHE II scores on admission (mean, 13 vs. 10) and more extensive pancreatic necrosis (mean, 55 vs. 47%). The post-ERCP group had a higher rate of infected necrosis (100 vs. 75%) and required earlier necrosectomy after the onset of pancreatitis (9 vs. 13 days). The rate of postoperative pancreatic and enteric fistulae was also higher (50 vs. 33%). Although the mortality rate in the post-ERCP group was lower (17 vs. 29%), they were significantly younger (50 vs. 62 years; p = 0.02) and all the survivors had residual long-term morbidity. ANP is more severe when ERCP-induced; infection introduced during the ERCP may, in part, account for this severity.