The time sequence and magnitude of endothelial cell proliferation was investigated in an experimental model of granulomatous colitis in rats, induced by intramural inoculations of mycobacterium Bacillus Calmette-Guerin. Colonic tissues were assessed by gross examination, histopathology, autoradiography, and immunohistochemistry. Gross examination of the colonic tissue showed thickening of the colonic wall, erythema, hemorrhage, and scattered ulcers. Histopathological findings were characterized by an acute transmural inflammation, progressing to chronic inflammation accompanied by regenerative changes in the glandular epithelium, goblet cell depletion, mucosal atrophy and fibrosis. Well-developed noncaseating granulomas were first observed at day 5 and were found to be a dominant feature up to day 17. Autoradiographic studies showed increased endothelial cell labeling up to 17% at 48 hr, compared to less than 1% labeling in control animals. Immunostaining for factor VIII-related antibody, an endothelial cell marker, showed increased numbers of microvessels and individual positive cells located in areas of inflammation as early as 24 hr. At day 5 these individual cells along with dilated neocapillaries were found surrounding the granulomas. This model of granulomatous colitis mimics many features of the human disease state. The early increase in endothelial cell proliferation that precedes granuloma formation during the course of the inflammatory response may suggest that the events leading to the expression of granulomatous colitis are dependent on endothelial proliferation.