Iatrogenic duodenal perforation associated with endoscopic retrograde cholangiopancreatography (ERCP) is a very uncommon complication that is often lethal. Perforations during ERCP are caused by endoscopic sphincterotomy, placement of biliary or duodenal stents, guidewire-related causes, and endoscopy itself. In particular, perforation of the medial or lateral duodenal wall usually requires prompt diagnosis and surgical management. Perforation can follow various clinical courses, and management depends on the cause of the perforation. Cases resulting from sphincterotomy or guidewire-induced perforation can be managed by conservative treatment and biliary diversion. The current standard treatment for perforation of the duodenal free wall is early surgical repair. However, several reports of primary endoscopic closure techniques using endoclip, endoloop, or newly developed endoscopic devices have recently been described, even for use in direct perforation of the duodenal wall.