Histochemical reactions which proved to be useful for the detection of early and late changes of corneal hydration after the injury of the rabbit cornea (Na+-K+-dependent adenosinetriphosphatase (ATP-ase), acid glycosidases, and reactions for glycosaminoglycans) were used for the evaluation of possible side effects on the rabbit cornea of compounds proposed as solvents or substances for the prolonged action of ophthalmic drugs. The following compounds were tested: Cellulose acetate phthalate (1%), propylene glycol (2%), polyvinylpyrrolidone (2, 5%), Tween 80 (1%), and polyethylene glycol 4000 (5%). Single dropping of cellulose acetate phthalate, polyvinylpyrrolidone and propylene glycol on the corneal surface did not change the corneal hydration. After repeated dropping of these drugs decreased activity of Na+-K+-dependent ATPase in the corneal endothelium followed by subendothelial swelling was found. On the other hand single application of Tween 80 and polyethylene glycol 4000 caused substantial decrease of Na+-K+-dependent ATP-ase activity in the corneal endothelium connected with profound corneal swelling. If dropping was repeated, inflammatory cells with high activities of acid glycosidases infiltrated the corneal stroma. After some days the release of these enzymes into substantia propria took place. This was accompanied by decreased staining of glycosaminoglycans indicating their local degradation. The histochemical approach was found to be more sensitive for the examination of the effect of drugs on corneal hydration than the biochemical examination. It can be concluded that Tween 80 and polyethylene glycol 4000 cannot be recommended for the preparation of eye drops.