Rhizopus oryzae is the most common cause of zygomycosis, a life-threatening infection that usually occurs in immunocompromised patients. A characteristic hallmark of zygomycosis is angioinvasion by the fungus, resulting in thrombosis and subsequent tissue necrosis. Interactions between R. oryzae and vascular endothelial cells are therefore likely of central importance to the organism's pathogenetic strategy. We studied the ability of R. oryzae to adhere to and damage human umbilical vein endothelial cells (HUVECs) in vitro. We report that R. oryzae spores and germ tubes adhere to HUVECs, whereas only spores adhere to subendothelial matrix proteins. Additionally, R. oryzae damages endothelial cells. This endothelial cell damage requires direct contact and subsequent phagocytosis of the fungus. Surprisingly, R. oryzae viability was not required for damage, but phagocytosis was required for dead R. oryzae to cause damage. These results elucidate the nature of R. oryzae-endothelial cell interactions, which are likely central to the angioinvasion and tissue necrosis seen during zygomycotic infections. The fact that dead R. oryzae damage human endothelial cells may, in part, explain the lack of efficacy of fungicidal agents during clinical disease.