The existence of a putative central prolactin-inhibiting factor (PIF) distinct from dopamine (DA) but dependent on DA mechanisms for release has been suggested from recent animal studies. We investigated the possibility of the existence of such a PIF in man by combining the use of monoiodotyrosine (MIT), an inhibitor of central DA synthesis, domperidone, a DA receptor antagonist that does not enter the blood-brain barrier and DA itself. 6 normal volunteers underwent three sets of studies: (1) PRL stimulation test to 400 µg TRH i.v., 1 g MIT orally or 5 mg domperidone i.v., (2) peripheral DA receptor blockade study in which either domperidone, MIT or TRH was administered at 120 min during a 240-min domperidone infusion (50 µg/min) which was preceded by a 5-mg bolus dose of domperidone i.v. and, (3) DA infusion study in which MIT was administered at 120 min during a 240-min infusion of DA in a dose (0.5 µg/kg · min) known to elevate peripheral DA concentration to levels reported for pituitary portal plasma. In the PRL stimulation tests, the mean ± SE peak response was significantly greater (p< 0.002) with domperidone (3,900 ± 840 mIU/l) than with MIT (1,880 + 400 mIU/l) or TRH (2,094 ± 450 mIU/l). In the peripheral DA receptor blockade study the initial domperidone-induced PRL response was not sustained during the domperidone infusion. Neither a second dose of domperidone nor MIT administration at 120 min resulted in a significant release of PRL. TRH administration resulted in a significant rise (p < 0.01) from 2,189 ± 470 mIU/l at 120 min to 2,950 ± 590 mIU/l at 135 min indicating that intracellular PRL stores had not been totally depleted by the initial stimulus. In the DA infusion study, the PRL suppression induced by the 240 min DA infusion (from 600 ±90 to 121 ±24 mIU/l) was not significantly altered by MIT administration (from 530 ±60 to 108 ±24 mIU/l). The failure of MIT, which acts centrally to inhibit DA activity, to induce a significant release of PRL during peripheral DA receptor blockade (with domperidone) does not support the existence of a central PIF distinct from DA. This conclusion is further supported by the failure of MIT to overcome PRL suppression induced by a peripheral infusion of DA. We conclude that in man, DA is the major PIF and that these studies do not support the presence of a central DA-mediated PIF. As dopaminergic inhibition of PRL release can be entirely accounted for by the blockade of DA action outside the blood-brain barrier, DA antagonists that cross the blood-brain barrier offer no special advantages over those