It is generally accepted that exogenous or endogenous prostaglandins (PGs) can give rise to acute increases in intraocular pressure (IOP) and to the development of flare and other signs of uveitis. It was recently shown, however, that low doses of PGE2 and/or PGF2 alpha topically applied to rabbit or owl monkey eyes significantly reduce IOP. The present experiments show that topical application of 10 to 500 micrograms of PGE2 also causes a highly significant IOP reduction in cat eyes lasting up to 48 hr with little or no development of flare or miosis, whereas similar application of PGF2 alpha causes, in addition to an IOP reduction, the development of profound pupillary constriction. Topical application of either PGF2 alpha or PGE2 to the eyes of rhesus monkeys also causes significant dose-dependent reduction in IOP. The hypotensive response in the rhesus monkey is not associated with detectable flare or consistent pupillary constriction, although at higher PG doses, hypotension tends to be preceded in both species by a brief (15 to 30 min) hypertensive phase. It is concluded that the eyes of different species show different patterns of IOP, miotic, and flare responses to topically applied PGs, the only consistent effect being a reduction in IOP. In some species, most notably in primates, a reduction in IOP is the predominant effect of PGs. Thus, PGs or their analogues may provide a new approach to the clinical control of IOP and the treatment of glaucoma.