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To evaluate the clinical outcome of intravitreal tissue plasminogen activator (tPA) and expansile gas injection as a minimally invasive treatment for submacular hemorrhage (SMH).This study was a retrospective clinical case series examining 104 eyes that received an intravitreal injection of 30–100 mcg of tPA and expansile gas (SF6 or C3F8) for SMH. The main outcomes evaluated were visual acuities (VA), anatomic displacement of submacular blood, and surgical complications.A total of 85, 77, and 81 eyes were available at 1 week, 3 months, and 12 months follow up, respectively. Postoperatively, ≥2 Snellen lines improvement were achieved in 43/85 eyes (51%) at 1 week, 49/77 eyes (63%) at 3 months, and 52/81 eyes (64%) at 12 months. Postoperative VA improvement was significantly associated with preoperative VA, submacular blood displacement, and the underlying cause of SMH. Diagnostic postoperative angiogram and clinical examination were possible at 8.2 ± 7.4 weeks and 9.5 ± 7.4 weeks, respectively. The observed complications included breakthrough vitreous hemorrhage in 8 eyes (8%) and retinal detachment in 3 eyes (3%).In this retrospective series, intravitreal injection of tPA and expansile gas was shown to be a safe and effective technique that can improve VA in most eyes with SMH and assist in the diagnosis of the underlying cause.