The effects of acetazolamide on intraocular pressure (IOP) were studied on rabbits previously nephrectomized to eliminate the renal effects of the drug. Administration of acetazolamide (5 mg/kg i.v.) reduced IOP from a baseline of 15.2 to 12.2 mm Hg 2 hr later. This dose was found not to alter arterial blood pH, pCO2, bicarbonate, or base excess. However, 4 hr after drug administration anterior chamber aqueous humor showed significant reductions in bicarbonate, pH, and base excess, whereas aqueous humor ascorbate was significantly elevated. Administration of acetazolamide 15 to 50 mg/kg i.v.) to nephrectomized rabbits caused significant acidosis and pCO2 retention, presumably related to red blood cell carbonic anhydrase inhibition. IOP reduction at these higher doses was greater than that which followed the 5 mg/kg administration.