Abstract Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation accompanied by changes in motility. It is known that regulatory peptides like substance P (SP) are important pro-inflammatory peptides which are also involved in neuronal conduction. To get clues for new diagnostic and therapeutic approaches we describe the SP receptor (NK-1) distribution in IBD compared to control intestinal tissue, on mRNA and protein level by three complementary techniques. Autoradiography showed differences within the intestinal wall of control patients; mucosal binding was 17 fmol/g and muscular binding was significantly ( p = 0.01) higher (98 fmol/g). In inflamed specimens of patients with IBD mucosal SP binding was increased compared to controls (55 ± 10 vs 18 ± 4 fmol/g mucosa, p = 0.002). However RT-PCR showed that the mRNA content of the NK-1 receptor in these samples was not increased. In non-inflamed samples of patients with Crohn’s disease (CD) and ulcerative colitis (UC) SP binding was similar as in controls, while mRNA was significantly decreased in CD patients (0.7 ± 0.02 vs 4.4 ± 0.7, p = 0.01) but not in UC patients (4.4 ± 0.7 vs 4.1 ± 1.4). Immunohistochemistry identified a broad spectrum of NK-1 receptor locations in control intestine. No aberrant expression in IBD was found. This study showed that although there was no difference in location of the SP receptors in IBD patients versus controls, the quantity of SP binding was significantly increased in the inflamed mucosa of IBD patients, while the mRNA level was not increased. Further a difference in mRNA level between non-inflamed tissue of CD and UC patients was shown, with mRNA in CD being lower. These changes in SP receptor expression during chronic inflammation suggest that SP receptors are a potential target for therapeutic regulation of the inflammatory response.