Studies were carried out of the effects of topically applied prostaglandin (PG) D2 and its metabolites and analogues on the intraocular pressure (IOP) in rabbits, and the results were compared with those of studies using PGE2 and F2 alpha. The application of PGD2 (0.4-250 micrograms) reduced the IOP, in a dose-dependent manner without causing a hypertensive phase. The hypotensive effect was observed within 30 minutes after the application and lasted for over 7 hours. Higher doses of PGE2 (10, 50 micrograms) or PGF2 alpha (50 micrograms) caused initial IOP elevation followed by a prolonged hypotensive phase. Lower doses of PGF2 alpha (2, 10 micrograms) caused a prolonged (over 7 hours) reduction in the IOP following a latency of over 2 hours. The IOP reduction by 2 micrograms of PGE2 lasted for 5 hours. No miotic response followed the use of these PG's. Conjunctival and iridal hyperemia, aqueous flare, irritation (defined by lid-closing), and aqueous protein content were examined at equi-hypotensive doses of the three PG's (50 micrograms for PGD2, 2 micrograms for PGE2, and 10 micrograms for PGF2 alpha). PGE2 was the strongest in causing these side effects, followed by PGF2 alpha. PGD2 did not cause any of these responses except for some development of conjunctival hyperemia. All of the 4 PGD2 metabolites were ineffective in reducing IOP. Among 6 PGD2 analogues, BW245C, PGD3, and PGD2 methyl ester more effectively reduced IOP than did PGD2. PGD1 and 16,16-dimethyl PGD2 were not effective.