1. Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2. Intravenously (i.v.) injected CP-96,345 (0.4-3.0 mumol kg-1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose- and time-dependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3. Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.0 mumol kg-1, i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10 mumol kg-1. 4. The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation.