The effects of griseolic acid (GA), a cyclic-AMP phosphodiesterase (PDE) inhibitor, and its 8′-pivaloyloxymethyl (POM) ester on intraocular pressure (IOP) in rabbits were investigated. When 50μ1 of 1 and 2% GA POM ester solutions were topically applied to one eye in normal rabbits, significant IOP decreases were detected at 2 hrs and at 1 to 5 hrs, respectively. Other than ocular hypotension, no other ocular effects were detected locally even after administration of 2% GA POM ester. A more marked reduction in IOP occurred after the intravitreal injection of the GA POM ester. IOP was also reduced when GA was used in an intravitreal injection but not when it was topically applied. The difference in permeability between GA and GA POM ester across the corneal epithelium may explain why GA failed to reduce IOP following topical administration. GA and the GA POM ester inhibited cAMP PDE in rabbit ciliary body at low concentrations, the I50being 0.075μM and 2.4μM, respectively, with 0.25pM cAMP as substrate. GA and the GA POM ester markedly increased cAMP levelsin vitroin iris-ciliary body specimens. Possibly, GA POM ester or its analogues may represent a new mechanistic class of ocular hypotensive agents.