We investigated the distribution and density of perivascular nerves in human mesenteric arteries and veins and their responses to noradrenaline (NA), ATP and neuropeptide Y (NPY) in control (non-inflamed) and inflamed bowel, using confocal microscopy and in vitro pharmacology. The density of innervation at the adventitial-medial border of arteries and within the medial muscle coat of veins was increased in inflammatory bowel disease (IBD). Expression of markers for both sympathetic nerves and sensory-motor nerves was significantly increased in IBD. Calcitonin gene-related peptide-containing sensory-motor nerves were present in control arteries and IBD, but not in control veins. The density of 5-hydroxytryptamine-containing nerves was variable in controls, but consistently increased (three to four times) in IBD. Vasoactive intestinal peptide (VIP) expression increased (doubled) in arteries and veins. Arteries and veins contracted to NA and ATP, but only veins constricted to NPY. ATP contractions were reduced in arteries and veins in IBD, while contractions to NA were only slightly reduced. Neuropeptide Y induced significantly greater (20%) contractions of IBD veins. In summary, the density of sympathetic and sensory-motor innervation of both mesenteric arteries and veins was increased in IBD. Both 5-hydroxytryptamine and VIP immunoreactivity were also increased. The responses of both arteries and veins to ATP, and to a lesser extent NA, were reduced in IBD while responses to NPY were greater in veins. Decreased responses to ATP indicate changes in purinergic-mediated transmission in the pathological state.