The intraocular effects of substance P (SP) were studied in rabbits by measuring the pupil diameter, intraocular pressure (IOP) and aqueous humor protein concentration. Most animals were pretreated with indomethacin to avoid any interaction with prostaglandins. Intracameral injection of 1-150 ng SP caused strong and persistent miosis without appreciably affecting the aqueous humor protein concentration or IOP. Intracameral injection of 0.8-11 .mu.g SP also induced an increase in IOP (7-8 mm Hg) without any apparent concomitant disruption in the blood-aqueous barrier. Outflow facility of aqueous humor decreased by a mean value of 50% after intracameral injection of 0.8-1.5 .mu.g SP. Since the increase in IOP could be prevented by iridectomy, it was probably caused by a pupillary block from the intense miosis induced by SP. No disruption in the blood-aqueous barrier could be detected after intra-arterial infusion of 100 .mu.g SP or intravitreal injection of 100 ng SP; the ciliary epithelium was practically insensitive to exogenous SP. Topical and subconjunctival administration of up to 1 mg SP did not cause any irritative response in the eye. With concentrations of SP causing intense miosis, the eye does not exhibit visible hyperemia and disruption of the blood-aqueous barrier. After certain irritative stimuli, miosis is mediated by a pathway separate from the hyperemia and disruption of the blood-aqueous barrier.