Neutrophils have an important role in mediating tissue injury in inflammatory bowel disease. The proinflammatory peptide formyl-methionyl-leucyl-phenylalanine (FMLP), which is produced by intestinal bacteria, is a potent chemotactic factor for human neutrophils and has been used experimentally to induce acute colitis in animal models. Its action involves specific receptors on the surface of the neutrophil. Increased mucosal permeability, which has been described in Crohn's disease, might contribute to the pathogenesis of the intestinal lesions in this disease by means of increased absorption of FMLP and other gut-derived bacterial products. To evaluate the interaction between FMLP and neutrophils in patients with inflammatory bowel disease, we have studied the binding characteristics and responsiveness of circulating neutrophils to this peptide. Neutrophils from patients with Crohn's disease but not those with ulcerative colitis were found to have significantly increased numbers of receptors for FMLP with similar affinity constants. This was associated with a significantly increased functional response to FMLP in chemiluminescence assays. Differences in neutrophils between Crohn's disease and ulcerative colitis are probably not intrinsic to the neutrophil but reflect their conditioning by the different inflammatory milieu of these diseases.