BACKGROUND Plasminogen activator has been shown to be released by epithelial cells following corneal injury. The demonstration of the release of plasminogen activator from cultured corneal epithelial cells has been used for developing a cytotoxicity test, the Corneal Epithelial Plasminogen Activator test, which compares changes in the level of plasminogen activator in tissue culture media following chemical exposure as an index of chemical injury. METHODS Cultured rabbit corneal epithelial cells were exposed to varying concentrations of several viscoelastics for 1 hour. Release of plasminogen activator into the tissue culture media following exposure to the viscoelastic agent was studied as an index of chemical injury. RESULTS The least cytotoxicity to cultured rabbit epithelium was associated with those viscoelastic agents containing methylcellulose. A 1-hour exposure to most concentrations of methylcellulose and chondroitin sulfate (Phacote) and methylcellulose (Occucoat) demonstrated release of greater amounts of plasminogen activator than was seen following a similar exposure to balanced salt solution, suggesting the greatest protective effect of these two viscoelastics. In contrast, sodium hyaluronate and chondroitin sulfate (Viscoat) showed decreased amounts of plasminogen activator release after a 1-hour exposure to cultured corneal epithelial cells demonstrating cytotoxicity. Polyacrylamide (Orcolon) and most diluted preparations of sodium hyaluronate (Healon and Healon Yellow) showed only mild reductions in the release of plasminogen activator, whereas undiluted sodium hyaluronate preparations were nearly as cytotoxic as Viscoat. CONCLUSIONS This study suggests that viscoelastic agents containing methylcellulose (Phacote and Occucoat) may be most protective of the corneal epithelium during ophthalmic surgery. The clinical success of several dilute viscoelastic solutions as tear substitutes was corroborated by the lack of cytotoxicity seen in this study. Viscoat and undiluted sodium hyaluronate preparations showed the greatest cytotoxicity to cultured rabbit corneal epithelium.