The occurrence, distribution and regional variation of neurones immunoreactive for the neuropeptides, vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), enkephalin (ENK), calcitonin gene-related peptide (CGRP), and substance P (SP) were investigated in human ureters by indirect immunohistochemistry. In addition, immunoreactivities to tyrosine hydroxylase (TH), a marker of noradrenergic neurones and to protein gene product (PGP) 9.5, a general marker of neurones, were also studied. Neurones displaying PGP-, NPY-, VIP- and TH-like immunoreactivity (-LIR) provided a rich innervation to the smooth muscle and blood vessels of the ureter, where they formed dense muscular and perivascular nerve plexuses. In contrast, there was only a moderate to sparse innervation by SP and CGRP-LIR neurones, most of which were distributed to blood vessels and to the sub mucosal layer, and only rarely to smooth muscle bundles. No ENK-LIR was detected in this study. Nerve fibre bundle densities were estimated for each of the localized neurochemicals according to a method described. NPY-LIR nerve fibre bundles were found to account for 80% of the total nerve fibre bundles (i.e. PGP-LIR) in the ureter. On the other hand, TH-LIR and VIP-LIR nerve fibre bundles each accounted for 50% of the total ureteral innervation, whereas SP- and CGRP-LIR nerve fibre bundles each comprised 20% of the total innervation. The abundance and pattern of tissues innervated by these immunoreactive neurones is consistent with the view that some of these neuropeptide substances co-exist with other peptide substances and/or with other known neurotransmitters, such as noradrenaline or acetylcholine. A gradient of innervation was found to exist for all the neurochemicals demonstrated in the ureter, whereby the lower ureter receives a greater density of innervation than the upper ureter. This finding suggests the human ureter is primarily innervated by fibres arising from or via the lower pelvis, i.e. the pelvic plexus. It also supports the view that the lower ureter may perform an important physiological role, such as coordinating the tone of this region during bladder filling and emptying.