We investigated in male rats whether the prolactin releasing effect of systemically infused histamine might be attributed to a vasodilatatory action of the compound. Intraarterial infusion of histamine (3.9 μmol) over 1 min increased the plasma PRL 10-fold. This effect was prevented by prior ia infusion of the H₁ receptor antagonist mepyramine and slightly augmented by prior ia infusion of the H₂ receptor antagonist cimetidine. At the same time histamine caused an immediate 38% decrease in mean arterial blood pressure, which remained 15% below the initial level during the rest of the 60-min observation period. The depressor effect of histamine was prevented by pretreatment with mepyramine and partly prevented for the first 5 min by pretreatment with cimetidine. Since the H₁ receptor seemed to be the predominant mediator of the histamine-induced hypotension and PRL release, a causative interaction is possible. However, when the histamine-induced decrease in blood pressure was prevented by simultaneous iv loading with saline the PRL response to histamine was still evident. Furthermore, when the histamine-induced decrease in blood pressure was mimicked by ia infusion of the vasodilator nitroprusside no effect was observed on PRL secretion. We conclude that the histamine-induced stimulation of PRL secretion is independent of the profound depressor action of the amine.