This study investigated a possible vascular origin for granulomas in Crohn's disease. Twenty-four consecutive resected specimens of small and large intestinal Crohn's disease were preserved by arterial perfusion-fixation with 10% formol saline, at mean arterial pressure (100 mm Hg). Fifteen specimens contained granulomas on routine examination of H&E-stained sections. These 15 specimens were examined in detail using a range of immunohistochemical staining techniques to identify vascular structures and granulomas. A total of 485 granulomas were found, 85% of which were identified as being directly involved in vascular injury. The majority (77%) of granulomas were deep to the mucosa; they were found most frequently in the submucosa (42%). The techniques used in this study enhanced the recognition of granulomatous vasculitis. The results suggest that the majority of granulomas in Crohn's disease form within walls of blood vessels. Vascular localization of granulomatous inflammation suggests that the intestinal microvasculature contains an early element in the pathogenesis of Crohn's disease.