The α<sub>v</sub>β<sub>3</sub> integrin interaction with the extracellular matrix (ECM) plays an essential role in inhibiting apoptosis in endothelial cells. We have recently shown that α<sub>v</sub>β<sub>3</sub> ligation on rat aortic endothelial cells (RAECs) specifically activates the transcription factor nuclear factor ĸB (NF-ĸB) and promotes cell survival. Inhibiting NF-ĸB nuclear translocation abolished the protective effect of α<sub>v</sub>β<sub>3</sub> ligands. Here, we report that ligation of α<sub>v</sub>β<sub>3 </sub>by its ligand, osteopontin (OPN), induces the phosphorylation and activation of inhibitory kappa B kinase beta (IKKβ) and promotes the specific degradation of inhibitory kappa Bα (IĸBα) in RAECs. Overexpression of a dominant negative (DN) IKKβ protein prevents IĸBα phosphorylation, NF-ĸB activation, and inhibits the protective effects of OPN. The NF-ĸB-inducing kinase (NIK) has been shown to be one of the upstream kinases involved in IKK activation. OPN-mediated NF-ĸB activity is increased upon NIK wild-type (WT) overexpression and blocked following NIK DN overexpression. In addition, NIK –/– mouse embryonic fibroblasts (MEFs) plated on OPN display reduced NF-ĸB activity and decreased IĸBα phosphorylation compared to NIK +/+ MEFs. Finally, functional inhibition of integrin β<sub>3</sub>-dependent NF-ĸB signaling decreases OPN-induced IĸBα, IKKβ and NIK phosphorylation. These studies for the first time show that the α<sub>v</sub>β<sub>3</sub>-NF-ĸB-dependent endothelial survival pathway is dependent on IĸBα, IKKβ, and NIK.