In a prospective study, specimens of resected small and large intestine from fifteen patients with Crohn's disease were prepared by heparin-saline vascular perfusion, followed by either resin casting of the mesenteric vascular supply and tissue maceration or glutaraldehyde perfusion-fixation, resin casting, and tissue clearance. The specimens were examined by macrophotography, histopathology, and either scanning or transmission electronmicroscopy. A pathogenetic sequence of events in Crohn's disease was seen—vascular injury, focal arteritis, fibrin deposition, arterial occlusion mainly at the level of the muscularis propria, followed by tissue infarction or neovascularisation. These features were confined to segments of intestine affected by Crohn's disease and did not occur in normal bowel. The findings suggest that Crohn's disease is mediated by multifocal gastrointestinal infarction. This pathogenetic process is compatible with many of the clinical features of Crohn's disease, and its recognition has important implications for the identification of the primary cause of the illness and advances in clinical management.