Hepatic portal venous air embolism is the rarest complication of gastrointestinal endoscopy, resulting from penetration of gas into the portal veins, and may occur during endoscopic retrograde cholangiopancreatography and endoscopic biliary sphincterotomy. The likely mechanism is intramural dissection of insufflated air into the portal venous system through duodenal vein radicles transected during the procedure. Hepatic portal air embolism may be fatal. Cerebral air embolism may also occur. So far 13 cases of air embolism after endoscopic retrograde cholangiopancreatography have been reported, with 4 cases of systemic spread that proved fatal. Death was due to pulmonary air embolism in 2 cases, and cerebral air embolism in another 2. We report on an additional such fatal case, concerning a 78-year-old male patient, who several years previously had undergone surgical gastroduodenal resection with cholecystectomy and papillotomy, and was admitted for recurrent ascending cholangitis secondary to bile duct stones. During the third endoscopic cholangioscopic procedure for removal of bile duct stones, sudden cardiopulmonary arrest occurred. Death was due to massive pulmonary air embolism. Cerebral air embolism was also found. Autopsy was performed. A spontaneous duodenobiliary fistula was found. On the basis of bench radiologic investigation (retrograde suprahepatic venography and anterograde portography), it was demonstrated that the air insufflated during duodenal endoscopy, which entered through the spontaneous duodeno-biliary fistula, penetrated into intrahepatic vein radicles injured secondarily to prolonged impaction of biliary sand and stones and infection, resulting in portal and hepatic venous gas and systemic air embolism.