Neuropeptides in perivascular nerves of vasa nervorum supplying blood to rat optic, sciatic, vagus and sympathetic chain nerve trunks are differentially vulnerable to streptozotocin (STZ)-induced diabetes. Immunohistochemical analysis of epineurial/perineurial nerve sheaths showed that 8 weeks after induction of diabetes, the density of neuropeptide Y (NPY)-immunoreactive nerve fibres in optic nerve sheaths was increased, while it was decreased in sciatic, vagus and sympathetic nerve sheaths. Vasoactive intestinal polypeptide (VIP)-immunoreactivity was increased in vasa and nervi nervorum of optic, sciatic, vagus and sympathetic chain nerve sheaths. Immunoassay of NPY confirmed increased levels in optic nerve sheaths and showed that substance P and calcitonin gene-related peptide levels increased in sciatic but not optic nerve sheaths. Neuropeptide levels in the intrafascicular nerve fibres were unaffected. This provides further evidence for a disturbance in the autonomic control of blood flow to peripheral and cranial nerve trunks via vasa nervorum in STZ-induced diabetes, which may lead to ischaemic changes, alter local axon reflexes and contribute to the pathogenesis of the disease.