Topical commercial phenylephrine HCl (Neo-Synephrine 10%) has been shown to cause an increase in corneal thickness and reversible vacuolization of corneal endothelial cells in rabbits. Using an in vivo model of regenerated corneal endothelial cells in the cat, we compared the cytotoxicity of phenylephrine-HCl 10% to regenerated and to normal, nonregenerated cells. Following removal of the epithelium, topical application of the drug causes the appearance of anterior and posterior bands of stromal edema and reversible vacuolization in both normal and regenerated endothelial cells. Phenylephrine was not more damaging to the regenerated cells. Polymorphonuclear leukocytes infiltrated between the regenerating cells 24 hr after treatment but did not appear to destroy them. Phenylephrine may therefore be implicated as a causative factor of corneal edema and postoperative inflammation.