Most perforations of the gastrointestinal tract during endoscopic retrograde cholangiopancreatography (ERCP) can be managed nonoperatively. Identifying patients who require operative management is problematic. A clinical endoscopy database was queried for patients who sustained ERCP perforation over a 13-year period. Records were reviewed and analyzed with approval of the Institutional Review Board. During the study period, 12,817 patients underwent ERCP; 24 (0.2%) had an endoscopic perforation. Twelve patients had a retroperitoneal perforation during sphincterotomy and all were successfully managed nonoperatively. Nine of these were undergoing treatment for sphincter of Oddi dysfunction. Twelve patients had perforation remote from the papilla. Of these, 10 required surgical intervention. Six patients had surgically altered anatomy (three postpancreaticoduodenectomy, three post-Billroth II gastrectomy) and one had situs inversus. Six of these seven required surgical intervention. Median length of stay of all patients was 7.5 days, morbidity was 25 per cent, and one patient died 16 days after surgery. Gut perforation after ERCP requires prompt surgical evaluation. Patients with sphincterotomy-related retroperitoneal perforation can be managed safely with nonoperative therapy in most instances. Patients with remote perforation usually need surgical intervention. Altered foregut anatomy leads to injuries that usually require operative management.