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Aims: To review and discuss the literature on recombinant tissue plasminogen activator (rtPA) for the treatment of a recent-onset submacular hemorrhage in patients with age-related macular degeneration. Methods: The administration technique of rtPA, the use of additional gas and vascular endothelial growth factor inhibitors (anti-VEGF), and the displacement rate of submacular hemorrhage and complications were noted from published reports, and a case series from the Rotterdam Eye Hospital (REH). Results: 38 studies with a total of 1,185 patients (1,176 eyes), and 28 patients from the REH were analyzed. Several methods for rtPA administration are available, which can be divided into two groups: submacular rtPA administration with vitrectomy; or intravitreal rtPA administration without vitrectomy. In both groups, the administration of gas and/or anti-VEGF agents could be additional. There appears to be no clear difference in complete displacement or complication rate between the more or the less invasive treatment groups. Conclusion: Although intravitreal injection of rtPA and gas only was reported to be as effective as subretinal rtPA with vitrectomy and gas, recent studies tend to use vitrectomy. These data underscore the need for a randomized controlled trial to choose the most effective and safe method of rtPA administration.