Invasive aspergillosis is characterized by two different types of angioinvasion. During pulmonary aspergillosis, hyphae are initially outside of the pulmonary vasculature and they invade the endothelial cell lining of the blood vessels by passing from the abluminal to the luminal surface. Some of these hyphal fragments can break off and circulate in the bloodstream. In severely immunocompromised hosts, these blood-borne hyphal fragments adhere to the luminal surface of the endothelial cells and they penetrate the endothelial cell lining of the vasculature by passing from the luminal to the abluminal surface. We have set up in vitro models of luminal and abluminal endothelial cell invasion by Aspergillus fumigatus. Luminal invasion by hyphae results in both endothelial cell damage and stimulation of tissue factor expression. Abluminal invasion causes less endothelial cell damage than luminal invasion, but greater induction of endothelial cells genes encoding cytokines, leukocyte adhesion molecules and tissue factor. These differences in the endothelial cell response to luminal versus abluminal infection may indicate significant differences in the pathogenesis of hematogenously disseminated versus locally invasive versus aspergillosis.