Purpose: The purpose of this study was to evaluate the treatment efficacy of vitrectomy combined with subretinal recombinant tissue plasminogen activator (r-tPA) and factors affecting visual improvement in patients with submacular hemorrhage (SMH) due to neovascular age-related macular degeneration (nAMD). Materials and Methods: Medical records of 17 consecutive patients diagnosed with SMH secondary to nAMD were retrospectively reviewed. The initial surgical procedure involved a 23-gauge transconjunctival vitrectomy, subretinal r-tPA application through a self-sealing inferior retinotomy, and sulfur hexafluoride gas for tamponade in all patients. The duration, size, and thickness of the hemorrhage and the pre-and post-operative visual acuity (VA) using a Snellen chart were recorded. VA was converted to logMAR for statistical analysis. Results: The average duration and size of the SMH were 12.8 +/- 18.2 days and 8.6 +/- 5.3 disc areas, respectively. The mean follow-up time was 16.9 +/- 4.7 months. A statistically significant visual improvement was found when comparing initial VA with postoperative best-corrected VA (BCVA) and final BCVA (Wilcoxon rank test, P = 0.01). There was no significant correlation between the size of the hemorrhage and postoperative BCVA and final BCVA (Spearman's rho test). There was no statistically significant correlation between the initial VA and postoperative BCVA and final BCVA (Spearman's rho test). There was no significant correlation between the duration of hemorrhage and postoperative BCVA and final BCVA (Spearman's rho test). The preoperative thickness of hemorrhage (747.5 +/- 30 mu m) was not correlated with postoperative BCVA or final BCVA (Pearson's test). Conclusions: Vitrectomy combined with subretinal r-tPA injection and gas tamponade is an effective surgical intervention to preserve VA in selected patients with apparent SMH.