Abstract—Survival of human vascular endothelial cells depends on their ability to activate the transcription factor nuclear factor-&kgr;B (NF-&kgr;B), a regulator of antiapoptotic genes, such as the X chromosome–linked inhibitor of apoptosis protein (xIAP). In the present study, we demonstrated expression of xIAP in the endothelial lining of normal human arteries and veins and elevated levels in highly malignant human endothelial tumors. Using retroviral infection of human endothelial cells, we identified two novel survival mechanisms mediated by xIAP in endothelial cells. First, xIAP can activate the transcription factor NF-&kgr;B, a known survival factor for human endothelial cells. This positive feedback loop induced by xIAP is mediated via phosphorylation and sustained degradation of inhibitor (I) &kgr;B&agr;. Second, xIAP can inhibit cell proliferation via downregulation of cyclins A and D1 and induction of the cyclin-dependent kinase inhibitors p21Cip1/Waf1and p27Kip1. Cleavage of xIAP by caspases during endothelial cell apoptosis disables both of these biological functions of xIAP. Thus, caspase-mediated cleavage of xIAP interrupts a positive regulatory cytoprotective loop between NF-&kgr;B and xIAP and increases the vulnerability of the cell to apoptosis by releasing it from an xIAP-mediated quiescent state.