Pathological angiogenesis is the hallmark of proliferative diabetic retinopathy (DR). In response to prolonged tissue injury, human retinal microvascular endothelial (HRMEC) cells form new blood vessels to ensure the supply of oxygen and nutrients; however, progressive fibrovascular proliferation can eventually lead to angiogenesis, retinal detachment, and blindness. Caspase-8, a responsible protease for apoptosis has also been shown to modulate pathological and developmental angiogenesis but whether it exerts this role in a hyperglycemic environment has not yet been explored. Here we demonstrate that high glucose decreased HRMEC cell viability and increased VEGF secretion. Pro-Caspase 8 expression was measured by RT-PCR and caspase 8 enzyme activity was confirmed by Caspase-Glo assay. In addition, Caspase-8 KD resulted in an inhibition of cell migration, and a significant reduction of p38 phosphorylation. Taken together, our data suggest that Caspase-8 may play a role in angiogenesis by promoting HRMEC migration via p38 MAPK phosphorylation.