To study the role of intestinal mast cells in Crohn's disease, a sensitive glass-fiber histamine assay was conducted in conjunction with mechanical dispersion of surgical specimens of 80 macroscopically actively inflamed colons, 40 non-inflamed colons, 40 actively inflamed ileums, and 16 non-inflamed ileums from patients with Crohn's disease and 96 control subjects. A strong correlation was found between the number of mast cells and the total histamine content in the controls (r = 0.682) (p < 0.05). The number of mast cells was decreased in Crohn's disease as compared with the controls (p < 0.01). Intestinal mast cells release histamine in a dose-dependent manner after challenges with anti-IgE (1.875-240.0 U/ml). A significant difference was noted in the release by anti-IgE between actively inflamed and non-inflamed colons of patients with Crohn's disease or control subjects (p < 0.01). Mast cells in actively inflamed tissue with Crohn's disease were shown to have different roles in the pathogenesis of inflammation.