In rats, the hypothalamic neurotransmitter histamine participates in regulation of vasopressin secretion and seems to be of physiological importance, because blockade of the histaminergic system reduces dehydration-induced vasopressin secretion. We investigated whether histamine is also involved in regulation of vasopressin secretion during dehydration in humans. We found that 40 h of dehydration gradually increased plasma osmolality by 10 mosmol/kg and induced a fourfold increase in vasopressin levels. Pretreatment with the H₂-receptor antagonists cimetidine or ranitidine significantly reduced the dehydration-induced increase in vasopressin levels ~40% after 34 and 37 h of dehydration, whereas this was not the case with the H₁-receptor antagonist mepyramine. Dehydration reduced aldosterone secretion by ~50%. This effect of dehydration was reduced by both H₁- and H₂-receptor blockade after 16 and/or 34 h of dehydration. We conclude that vasopressin secretion in response to dehydration in humans is under the regulatory influence of histamine and that the effect seems to be mediated via H₂-receptors. In addition, the regulation of aldosterone secretion during dehydration also seems to involve the histaminergic system via H₁ and H₂ receptors.