Substance P, a neurotransmitter found in colonic mucosa, can alter gut immunologic, vascular, and motor phenomena. Thus, it may have an important role in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). By radioimmunoassay of the extracts of endoscopically obtained rectal mucosal biopsies in affected patients, we evaluated mucosal substance P levels. Non-inflammatory bowel disease patients undergoing lower endoscopies and biopsies served as controls. There were significantly increased concentrations of substance P in patients with UC, compared with controls (p < 0.05) and compared with patients with CD (p < 0.005). The mucosal levels in CD patients were significantly lower than in controls (p < 0.05). Patients with active rectal CD had lower levels than patients with no evidence of active rectal disease. For the CD and UC patients, there was a strongly positive correlation between rectal mucosal substance P concentrations and total histologic inflammation scores (r = 0.7, p = 0.001). A strong correlation existed for rectal mucosal substance P concentrations and mucosal mononuclear cell scores (r = 0.7, p = 0.001) and for rectal mucosal substance P concentrations and the combined scores of mucosal neutrophils and eosinophils (r = 0.7, p = 0.002). In conclusion, the rectal mucosal substance P concentrations in patients with UC and CD are significantly different. Thus, substance P may have a different role in the pathogenesis of each of these entities. It is possible that the elevated concentrations in patients with UC are contributing to the increased inflammation seen in these patients. Alternatively, measured mucosal substance P levels may simply reflect the end result of the different inflammatory processes in UC and CD, rather than the cause. It is possible that the inflammatory cells are contributing to the measured concentrations.