We performed a prospective, randomized double blind study comparing the cardiovascular and intraocular pressure (IOP) effects of unilateral therapy with clonidine 0.125% and apraclonidine hydrochloride 1.0% in 15 normal and 15 ocular hypertensive volunteers. Baseline values were obtained prior to instillation. One drop of test medication (clonidine, apraclonidine or placebo) was instilled unilaterally, and the post-instillation measurements were taken at 1, 2, 4, 6 and 8 hours. Apraclonidine 1% produced a maximum 31.4% +/- 6.9% (4.83 +/- 1.17 mmHg) decrease in mean IOP in ocular normotensive volunteers and 33.9% +/- 6.9% (10.10 +/- 2.45 mmHg) in ocular hypertensive patients (p < 0.001). These values were 22.1% +/- 6.9% (2.90 +/- 1.94 mmHg) and 22.7% +/- 6.9 (6.80 +/- 2.31 mmHg), respectively in clonidine group (p < 0.001). In apraclonidine group, there were no changes in contralateral IOP, blood pressure or pulse rate. Clonidine produced a significant decrease in contralateral IOP, but this reduction was not statistically significantly different than that of placebo. In clonidine group, there was no change in pulse rate, but a significant decrease in blood pressure. Eyelid retraction, conjunctival blanching and mydriasis were noted in eyes treated with apraclonidine. However there were no statistically and clinically significant changes in pupil size or interpalpebral fissure width with clonidine. This study suggests that apraclonidine appears to be safer and more effective ocular hypotensive agent than clonidine in treatment of glaucoma.