Purpose: To characterize the timing of large submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) relative to anti–vascular endothelial growth factor (VEGF) therapy. Design: Retrospective, consecutive case series. Participants: The study included 46 eyes of 46 patients with large SMH resulting from neovascular AMD selected to undergo pars plana vitrectomy with subretinal tissue plasminogen activator at the Mid Atlantic Retina group of the Wills Eye Hospital. Methods: Patient charts were reviewed to identify baseline characteristics and anti-VEGF treatment details. OCT was used to evaluate pigmented epithelial detachments, SMH, and subretinal fluid before and after SMH. Main Outcome Measures: The timing of SMH in relation to last anti-VEGF injection, the anti-VEGF treatment status (i.e., naive, stable, or recently extended or shortened) at the time of SMH, and the length of the anti-VEGF treatment interval at the time of bleeding. Results: Submacular hemorrhage occurred in 15 patients (36%) who were treatment naive. In patients treated with anti-VEGF, 19 (45%) had a stable treatment interval, 5 (12%) had a recently extended interval, and 3 (7%) had a shortened interval. The average treatment interval at the time of SMH was 6.8 weeks with a median of 7 total injections before SMH. Seven treated patients (26%) experience an SMH while having a 4-week dosing interval. The average time between last injection and SMH was 29 days. Forty-eight percent of patients treated with anti-VEGF agents experienced an SMH within 30 days of anti-VEGF injection. Chi-square analysis found SMH more likely to occur within 30 days of anti-VEGF injection than after 30 days. Conclusions: Large SMH in neovascular AMD in a treat-and-extend regimen does not seem to be associated with prolonged dosing intervals or recent interval extension, and a large proportion of such hemorrhages are likely to be a result of mechanisms other than loss of effective VEGF inhibition.