Escherichia coli O104:H4-associated hemolytic uremic syndrome (HUS) is characterized by Shiga toxin-induced vascular damage. As indicated by recent studies, dysregulation of the angiopoietin (Angpt)/Tie2 ligand receptor system may be crucial for endothelial dysfunction in HUS. Early Angpt-2 levels quantified in 48 adult HUS patients were predictive for a complicated clinical course, in particular for need of hemodialysis and mechanical ventilation as well as occurrence of seizures. In vitro challenge of human umbilical vein endothelial cells with patients' sera indicated an injurious mediator role of Angpt-2 opening future perspectives for mitigating endothelial activation in HUS.