We evaluated the safety and efficacy of intravitreous recombinant tissue plasminogen activator (rTPA) and gas for the treatment of submacular hemorrhage in age-related macular degeneration (ARMD). From January 2000 to April 2002, we enrolled 15 patients with submacular hemorrhage secondary to ARMD. All patients received 100 microg rTPA and 0.3 mL perfluoropropane intravitreously. Postoperatively, all patients were kept in a supine position for 4 hours followed by a face-down position for 4 days. Anatomic and functional results were evaluated during a follow-up period of 6 to 19 months. Submacular blood was completely displaced in 12 patients (80%) and partially in three (20%). Best postoperative visual acuity improved in all 15 eyes; in seven eyes (47%), the improvement was two or more lines. Final visual acuity improved in 12 eyes, remained stable in two eyes, and worsened in one eye. Onset of hemorrhage within 21 days was associated with better gains of lines in best postoperative (p = 0.0256) and final visual acuity (p = 0.044). Although two patients developed mild breakthrough vitreous hemorrhage within 1 day after treatment, no rTPA-related retinal toxicity was observed. Intravitreous injections of rTPA and gas are safe and effective in improving visual acuity in patients with submacular hemorrhage secondary to ARMD. Although the final visual outcome is often limited by the progression of the disease, significant and stable visual recovery over an extended follow-up period is possible using this easy and convenient technique.