To investigate the risk factors for breakthrough vitreous hemorrhage (VH) after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection in age-related macular degeneration (AMD) accompanied by submacular hemorrhage (SMH). We retrospectively reviewed the medical records of patients diagnosed with AMD combined with SMH, and enrolled 31 patients. We formed an age- and sex-matched control group of patients with submacular hemorrhage who did not develop breakthrough VH after intravitreal injection during 6 month follow-up. The mean patient age was 70.8 ± 10.3 years in the breakthrough VH group. Of the 31 patients, 8 were diagnosed with choroidal neovascularization (CNV), 22 with polypoidal choroidal vasculopathy (PCV), and 1 with retinal angiomatous proliferation (RAP). PCV was associated with a significantly higher incidence of VH (odds ratio, 35.01; p = 0.001). The size of the SMH was 22.7 ± 12.4 disc areas (DAs) in the breakthrough VH group and 5.4 ± 6.9 DAs in the control group, and was thus significantly related to the development of VH (p < 0.001). The risk of VH was significantly higher in those taking anticoagulants (p = 0.014). There was no significant difference between the types of anti-VEGF agents. When taking anticoagulant medications, a SMH of large diameter, and PCV subtype were risk factors for breakthrough VH after anti-VEGF injection.