Diabetes mellitus (DM), as chronic stress, activates the hypothalamo-pituitary-adrenocortical axis. We examined whether vasopressin (AVP) and the hypothalamic paraventricular nucleus (PVN) participate in DM-induced chronic stress symptoms. AVP-deficient Brattleboro or PVN-lesioned Wistar rats were used with heterozygous or sham-operated controls. The rats were studied 2 weeks after a single injection of streptozotocin. The appearance of DM (enhanced water consumption and blood glucose elevation) and the chronic stress-like somatic changes (body weight decrease, thymus involution, adrenal gland hypertrophy) were not influenced by the lack of AVP. In contrast, PVN-lesion significantly attenuated DM-induced thymus involution, adrenal gland hypertrophy as well as the increase in water consumption. The CRH mRNA in PVN was diminished by DM and elevated by the lack of AVP without interaction. DM elevated the POMC mRNA in the anterior lobe of the pituitary. The lack of AVP had no effect while lesioning the PVN significantly diminished the elevation. The elevated basal corticosterone plasma levels detectable in DM were influenced neither by the lack of AVP nor by lesioning the PVN. Thus, the lack of AVP had no influence on DM-induced chronic stress symptoms, but lesioning the PVN attenuated part of them. However, the lack of elevation in POMC mRNA after PVN-lesion together with the maintained corticosterone elevation suggests that direct adrenal gland activation occurs in untreated DM.