An aortoduodenal fistula (ADF) is believed to stem from erosion of a rigid prosthesis into the fixed retroperitoneal duodenum. Experimental and clinical data do not support a mechanical etiology, but indicate that the pathogenesis is an unrecognized graft infection with pseudoaneurysm formation. A 5 cm segment of Dacron was interposed in the infrarenal aortas of 24 dogs that were divided into four groups of six animals each. In group 1 (control) the duodenum was fixed by sutures to the proximal anastomosis of the Dacron graft. At 6 weeks' follow-up, no ADFs or deaths had occurred among this group. In group 2 the duodenum was fixed to the aortoprosthetic anastomosis and the dogs received an intravenous infusion of 10(8) S. aureus; two of these dogs developed ADF (P less than 0.01). In group 3 the duodenum was incorporated as a patch on the anterior aspect of the aortoprosthetic suture line, creating a false aneurysm; three of these animals died as a result of ADF. A false aneurysm was created in group 4 dogs, as in group 3, but in addition, 10(8) S. aureus was administered intravenously; here five to six animals developed ADF. Clinical and bacteriological evidence of graft infection was present in seven of 11 patients with ADF who were seen over an 18 year period. Five had pseudoaneurysm formation at the proximal anastomosis. Operation was performed in eight patients; three had closure of the aortic leak and repair of the duodenum with omentum interposition. All resulted in recurrent fistula and delayed hemorrhage. Simple graft excision in two patients without reconstitution of peripheral circulation resulted in lower extremity gangrene. The three survivors had graft excision and axillofemoral bypass. These data suggest that the etiology of ADF is primary low-grade infection. Successful operation necessitates excision of the graft, duodenal closure, and an extraanatomical axillofemoral bypass graft.