The effects of 3rd ventricle injection of metiamide, an H2-histamine receptor antagonist and pyrilamine, an H1-histamine receptor antagonist, on the increase of plasma prolactin induced by two doses of histamine in normal male rats were studied. Metiamide did prevent the stimulating action of histamine whereas pyrilamine was not effective. Histamine-induced prolactin release was also blocked by low doses of the 2 antihistamines given in combination. Metiamide per se has no effect but high doses of pyrilamine increased plasma prolactin levels and augmented the hormone response to histamine. The results suggest mediation of H2-receptors in the facilitatory action of histamine on prolactin release.