Esophageal adenocarcinoma arises from Barrett's esophagus, which is induced by gastro-esophageal reflux. This refluxate often contains duodenal contents, whose backflow triggers gastric carcinoma, suggesting the hypothesis that refluxed duodenal contents cause esophageal carcinoma. This study examines the role of duodenal and gastric reflux in the absence of exogenous carcinogens in esophageal carcinogenesis. Wistar male rats, 120 in all, each weighing approximately 250 g, were used. Three experimental procedures were performed to produce gastro-duodeno-esophageal reflux, duodeno-esophageal reflux and gastro-esophageal reflux, for comparison with 2 control procedures, Roux-en-Y reconstruction and a sham operation. The animals were fed a standard diet and were examined 50 weeks after surgery. While no carcinoma was found among the 16 gastro-esophageal-reflux, 11 Roux-en-Y and 12 sham-operation animals, 10 of the 12 animals with gastro-duodeno-esophageal reflux (83%) and 10 of the 13 with duodeno-esophageal reflux (77%) developed esophageal carcinoma. The difference between groups was significant (p < 0.001). Two animals with gastro-duodeno-esophageal reflux had esophageal double and triple carcinomas respectively. Of the 23 carcinomas, 16 were adenocarcinoma, 4 adenosquamous carcinoma, and 3 squamous-cell carcinoma. Adenocarcinoma developed from the columnar-lined epithelium near the esophago-jejunostoma, while adenosquamous and squamous-cell carcinoma arose from the squamous esophagitis. These observations demonstrate that refluxed duodenal contents per so are responsible for esophageal carcinogenesis.