The effect of ethacrynic acid, a potential outflow agent for the treatment of glaucoma, was studied in a series of 25 pairs of human eyes in perfusion organ culture.Concentrations varied from 0.01 mM to 2.4 mM and were used in single or repetitive doses.Intraocular pressure was continuously recorded for up to two weeks after exposure. Eyes were then fixed and the meshwork examined histologically.Ethacrynic acid in single doses of 0.05 mM, 0.3 mM, and 0.6 mM increased facility of outflow at least 40% when compared with fellow control eyes. The duration of effect was approximately 18 hours, during which time the intraocular pressure gradually returned to baseline. Histologic examination revealed dose related effects on the trabecular cells, ranging from clumping of nuclear chromatin in some eyes to cellular swelling, disruption of cytoplasmic membranes, and cell necrosis in other eyes at concentrations of 0.1 mM and higher. No recovery or reversal of these changes was noted with time, even two weeks after a single exposure to the drug. Although ethacrynic acid is effective in temporarily lowering intraocular pressure in the human eye, a low therapeutic index may limit its clinical usefulness.