The effects of topical and intracameral serotonin and topical, intracameral and intravenous selective (5-HT2) serotonin antagonist, ketanserin, on the intraocular pressure (IOP) were studied in the rabbit. The IOP was measured using a pneumotonometer or electromanometrically using intracameral needles. Topical 2% serotonin decreased the IOP by 4.0 +/- 0.9 mmHg (delta IOP, p less than 0.01) in normal eyes. This hypotensive effect was reduced after sympathetic denervation. Intracameral serotonin (4.0 micrograms), on the other hand, caused a rise in the IOP, and a breakdown of the blood-aqueous barrier, which were not inhibited by sympathectomy. Topical 2% ketanserin lowered the IOP in the ipsilateral eye by 4.1 +/- 0.4 mmHg (p less than 0.001). A decrease in the IOP of the contralateral eye was observed as well. After sympathectomy the hypotensive action of topical ketanserin on the IOP was inhibited. Intravenous ketanserin (0.5 mg/kg b.w.) lowered the IOP significantly and in the sympathectomized eyes a small decrease occurred, as well. In anesthetized animals topical, intravenous or intracameral ketanserin didn't cause a decrease in the IOP. The present study indicates the controlling effect of serotonin and ketanserin on the IOP. The hypotensive actions of topical serotonin and ketanserin on the IOP are at least partly dependent on the intact sympathetic innervation of the eye. However, the action of ketanserin seems to mediate also through central pathways.