The authors injected 25 micrograms of recombinant tissue plasminogen activator (tPA) into the anterior chamber or vitreous cavity of 23 eyes of 22 patients with severe intraocular fibrin formation that developed after vitrectomy surgery for complicated cases of proliferative vitreoretinopathy (PVR) (13 eyes), diabetic traction retinal detachment (TRD) (7 eyes), or endophthalmitis (3 eyes). Tissue plasminogen activator injected an average (+/- standard deviation) of 73 +/- 63 hours after vitrectomy surgery resulted in complete fibrinolysis in 21 of 23 eyes and partial fibrinolysis in one eye. The mean time to fibrin resolution was 3.0 +/- 1.0 hours. Four eyes required repeat tPA injection for recurrent fibrin formation; repeat injection resulted in complete fibrinolysis in each case. The mean follow-up duration after tPA administration was 6 months. At the final follow-up examination, the retina was totally attached in 18 of 23 eyes and was partially attached in 2. Visual acuity improved in 12 eyes (52%); it was at least 20/400 in 8. Complications of tPA injection included hyphema (2 patients) and corneal stromal thickening (2 patients). Mild, transient, periocular pain that was easily managed with non-narcotic analgesia developed in three patients.