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Many patients with neovascular age-related macular degeneration (nvAMD) respond inadequately to therapies targeting vascular endothelial growth factor (VEGF). Following treatment of patients with nvAMD with anti-VEGF therapy, we report decreased expression of VEGF but increased expression of a second angiogenic mediator, angiopoietin-like 4 (ANGPTL4). Increased ANGPTL4 expression is a consequence of accumulation of hypoxia-inducible factor (HIF)-1α in response to VEGF/kinase insert domain receptor (KDR) inhibition in the retinal pigment epithelium. By preventing the increase in HIF-1α accumulation in response to anti-VEGF therapy, combining 32-134D with aflibercept was more effective for choroidal neovascularization (CNV) treatment in mice than either drug alone. This suggests that combining 32-134D with current therapies may overcome the inadequate response of patients with nvAMD to anti-VEGF monotherapy.