We studied the dose-dependent retinal toxicity of the available commercial preparation of human recombinant tissue plasminogen activator in the normal rabbit eye. Tissue plasminogen activator was injected into the midvitreous cavity of albino rabbits in doses (per 100 microL) of 25, 50, 75, and 100 micrograms. Control eyes received 100 microL of balanced salt solution or tissue plasminogen activator vehicle. No evidence of a retinal toxic reaction was seen in eyes receiving 25 micrograms of tissue plasminogen activator. One of four eyes injected with 50 micrograms showed loss of photoreceptor cells by light microscopy. Severe retinal damage was seen by ophthalmoscopy, electroretinography, and light microscopy in three of four eyes receiving 75 micrograms of tissue plasminogen activator and in all eyes treated with 100 micrograms of tissue plasminogen activator or equivalent vehicle. These results suggest that the commercial recombinant tissue plasminogen activator formulation has a narrow margin of safety in nonvitrectomized eyes and that a component of the vehicle is the toxic factor.