A20 binding inhibitor of NF-kappaB activation-2, ABIN-2, is a newly identified intracellular protein that interacts with the zinc finger protein A20. ABIN-2 inhibits nuclear factor-kappaB (NF-kappaB) activity and is a possible effector of A20 regulation of NF-kappaB. Although A20 is a potent inhibitor of endothelial apoptosis, the effect of ABIN-2 on apoptosis is not known. ABIN-2 also interacts with the endothelial receptor Tie2. This receptor is essential for blood vessel formation and promotes endothelial survival. Here we examine the effects of ABIN-2 on endothelial cell apoptosis and its potential involvement in Tie2-mediated endothelial survival. ABIN-2 was found to inhibit endothelial apoptosis and rescue cells from death following growth factor deprivation. The inhibitors of phosphatidylinositol-3 kinase, wortmannin and LY294002, suppressed ABIN-2 inhibition of endothelial cell death. Deletion of the carboxy-terminus of ABIN-2 removed its ability to inhibit apoptosis. Expression of truncated ABIN-2 prevented the Tie2-activating ligand angiopoietin-1 from inhibiting endothelial cell death.