Repeated topical administration of 2.5% trifluormethazolamide, a halogenated derivative of methazolamide, resulted in a unilateral decrease in intraocular pressure in rabbits. Mean (+/- S.E.M.) baseline intraocular pressure (19.8 +/- 2.1 mm Hg) was significantly (P less than .05) decreased 30 minutes (16.1 +/- 2.2 mm Hg) and 60 minutes (15.8 +/- 2.7 mm Hg) after drug administration. Trifluormethazolamide did not alter outflow facility. Aqueous humor flow calculated from the tonographic data was reduced 44% and flow measured by fluorophotometry was reduced 29%. Topical delivery of trifluormethazolamide decreased the level of carbon dioxide in the aqueous humor in the treated eye in a manner similar to that observed after systemic administration of carbonic anhydrase inhibitors. Topical administration of 10% acetazolamide did not decrease intraocular pressure. However, topical administration of either trifluormethazolamide or acetazolamide before oral administration of water resulted in a blunting of the water-induced ocular hypertensive response.