Disrupting DGKε in endothelial cells (ECs) leads to prothrombotic phenotype without complement activation. After receptor activation, phospholipase C (PLC) mediates hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP₂) to DAG. Arachidonic acid–containing DAG is catalyzed to PA by DGKε. Disruption of DGKε increases p38 activation and surface expression of intercellular adhesion molecule-1 (ICAM-1), E-selectin (E-Sel), and tissue factor (TF). Loss of DGKε also increases endothelial apoptosis, impairing migration and angiogenic response. DGKε depletion decreases the surface expression of membrane cofactor protein (MCP), increases the expression of decay accelerating factor (DAF), and does not alter the level of CD59. Despite these changes, complement C3b deposition was not altered in DGKε-deleted cells.