In intact rats, .alpha.-adrenergic receptor blocking agents phenoxybenzamine (PBZ) and phentolamine markedly potentiated the pressor response to oxytocin and vasopressin (VP). In the presence of PBZ or phentolamine blockade, the dose-response curves of oxytocin and VP were shifted to the left, resulting in an apparent doubling of the pressor potency of the neurohypophysial peptides. The .beta.-adrenergic blocking agent, propranolol, had no significant effect on the pressor response to oxytocin or VP. Combined PBZ and propranolol blockade did not alter the potentiating activity of PBZ. The PBZ-potentiating effect seems to be specific to the neurohypophysial peptides, since the pressor response to angiotensin was not potentiated by PBZ. The potentiating effect of PBZ on VP could be demonstrated in isolated rat aortic strips. The site of action of PBZ appears to be directly on the vascular smooth muscle. In aortic strips the effect of PBZ was seen only if norepinephrine (NE) was also added to the bathing medium. NE alone had no significant effect on the contractile response to VP. The requirement of both PBZ and NE for the potentiating effect suggests that an interaction between these 2 agents is involved in the PBZ potentiation of VP response. The possibility that NE and not PBZ is the direct agent causing the potentiation of VP response is discussed.