The diagnosis, differentiation, and management of severe pancreaticoduodenal complications occurring after therapeutic endoscopic sphincterotomy and related procedures on the ampulla of Vater were reviewed for 254 patients. Five patients had duodenal (peri-Vaterian) perforation and six patients had clinically significant pancreatitis. Most patients were not suspected of having a significant complication the night of the procedure despite abdominal pain. Computer tomography proved to be the most accurate test for establishing the existence of a significant complication. A periduodenal collection of fluid (abscess) without significant pancreatic enlargement was the predominant complication in patients with duodenal perforation. In patients who had pancreatitis after peri-Vaterian procedures, generalized pancreatic enlargement and peripancreatic edema were most prominent. Four of the five patients with duodenal perforation required surgical drainage; all recovered. In contrast, four of the six patients with pancreatitis had medical therapy. One patient with pancreatitis died after multiple pancreatitic debridements were done. A second patient with pancreatitis who underwent exploration eventually recovered. Pancreaticoduodenal complications after therapeutic endoscopic sphincterotomy and related procedures are difficult to diagnose early; they should be suspected early and approached aggressively to limit morbidity and death.