The purpose of this study is to investigate the efficacy of tissue plasminogen activator (tPA) in the treatment of total hyphema following ocular trauma or intraocular surgery. Three patients (3 eyes) representing unresolved total hyphema for more than 5 days and uncontrolled high intraocular pressure received intracameral injections of 10 microgram of recombinant tPA. Intracameral tPA injection resulted in complete resolution of hyphema in all 3 eyes. Resolution occurred mostly within 24 to 48 hours after injection. Possible side effects of tPA injection, such as increased intraocular pressure and corneal edema, were not observed. However, 1 eye had vitreous hemorrhage after repeated injections of tPA. Intracameral injection of tPA seems to be a safe and effective method for the treatment of unresolved total hyphema. However, repeated intracameral tPA injections may cause unwanted complications such as vitreous hemorrhage.