To eliminate uncertainties about compliance, 15 patients with glaucoma (intraocular pressure [IOP] > 22 mm Hg and < 40 mm Hg) were hospitalized to participate in a clinical trial of the ocular hypotensive effectiveness of the new prostaglandin F2 alpha analogue prodrug, PhXA41 (13,14-dihydro-17-phenyl-18, 19, 20-trinor-PGF2a-isopropyl ester; latanoprost [World Health Organization generic name]). At 9 PM on each of five consecutive days, one of the investigators applied one drop of a 0.006% solution of PhXA41 (representing approximately 2 micrograms of PhXA41 per treatment) to one eye of nine patients and one drop of placebo to one eye of six patients. This was followed by an evaluation of potential local side effects at 9:30 PM. Complete examinations, including tonometry (Goldmann), were also performed at 8 AM and 8 PM on days 1 to 6, as well as at noon and 4 PM on days 1, 2, and 6. Except for mild conjunctival hyperemia in two PhXA41-treated eyes (once each at 8 AM), no side effects were observed or reported by any patient. Starting with the first IOP measurement after the first treatment (8 AM on day 2), IOP was reduced by 20% to 30% in the eyes treated with PhXA41. This reduction was highly significant (P < .01 at 12 time points and P < .05 at the remaining two measurements) throughout the study. The IOP reduction did not become attenuated during the 23 hours after treatments. At 11 hours after the last treatment, the mean (+/- SD) IOP difference between PhXA41-treated and contralateral control eyes was -5.5 +/- 2.8 mm Hg, as compared with -6.1 +/- 1.8 mm Hg 12 hours later. PhXA41 must, therefore, be regarded as an excellent candidate for use as a once-a-day glaucoma medication.