During a 29-month trial, 65 patients with acute gallstone pancreatitis were randomly selected for biliary tract explorations either within 73 hours of admission (36 patients) or at three months following remission with nonoperative measures (29 patients, with five others awaiting elective operation). The details of surgery were identical, i.e., cholecystectomy, transduodenal sphincteroplasty, and pancreatic duct septotomy. Major bile ducts were cleared of stones by Fogarty catheter passage up the sphincteroplasty. At early operation, pancreatitis was in the acute edematous form in 29 patients, necrotizing in six, and hemorrhagic in one. Acute inflammatory changes were also noticed in three patients who underwent late operation. The locations of the gallstones in patients undergoing early versus delayed operations were, respectively: 97% and 100% in gallbladder, 75% and 28% within common or hepatic ducts (p < 0.02), and 31% and 0% free in duodenum (p < 0.01). The distal choledochus and ampulla were inflamed in 89% of the patients who underwent early operations, but in merely 17% operated upon electively (p < 0.01). Concomitant acute cholecystitis was present in 31% of the patients if surgery was performed during the initial admission, but in only 3% of the patients at delayed operation (p < 0.05). Most striking was the sudden "gush" of pancreatic juice when the ampullary sphincter was first stretched or cut during sphincteroplasty at early operation. Precipitous falls in serum amylase levels then followed over the next 24 hours. No significant differences were noticed in the mortality rate (one death after early operation, two after a delayed procedure), major morbidity rate (in four and three patients, respectively), or in duration of the initial hospitalization period (early operation: 13.5 days, delayed operation: 16.7 days). However, a second admission to the hospital for the delayed operation (12.1 days) was avoided by early operation. These data support the concept that biliary pancreatitis is probably initiated by gallstone passage through, or lodgement at, the ampulla of Vater. The resultant ampullary edema with or without gallstone impaction appears to be the anatomic cause for major pancreatic duct obstruction and the consequent pancreatitis. Early and appropriate surgical relief of the biliary tract pathology via a transduodenal sphincteroplasty can obviate the need for a second admission to the hospital without increasing, significantly, the attendant morbidity and mortality rates.