Protein kinase B (Akt1) holds a central role for cellular growth, development, and survival, but the cellular pathways of Akt1 that prevent inflammatory demise in the vascular system remain undefined. Employing a constitutively active form of Akt1 (myristoylated Akt1) in endothelial cells (ECs), we demonstrate that Akt1 not only modulates intrinsic pathways of EC injury that involve genomic DNA destruction, but also uniquely regulates extrinsic mechanisms of cellular inflammation mediated by phosphatidylserine exposure (PS) and microglial activation. Activation of Akt1 is necessary and sufficient to prevent apoptotic EC destruction, since inhibition of the phosphatidylinositide-3-kinase pathway as well as transfection of ECs with a dominant-negative Akt1 mutant abrogates vascular protection. Furthermore, we illustrate that control of microglial activation by Akt1 is directly dependent on the modulation of EC membrane PS exposure. Akt1 provides a novel capacity to foster EC survival through the prevention of cysteine protease degradation of Bcl-x(L) that is intimately linked to the specific inhibition of caspase 1-, 3-, and 9-like activities and the modulation of mitochondrial membrane potential and cytochrome c release. Our work elucidates the critical role of Akt1 during cellular inflammation and identifies new downstream targets of Akt1 that may offer therapeutic potential against vascular disease.