Hyperglycemia or high blood sugar is one of the major pathological characteristics of diabetes. The endothelium is the inner layer of the vascular wall and is directly exposed to various stimuli in blood vessels. As a characteristic of diabetes, chronic high glucose is known to be harmful to endothelial cells. In this study, we found that vildagliptin, an available type 2 diabetes agent, protects primary human aortic endothelial cells (HAECs) against damage induced by high glucose. Our data indicate that vildagliptin improves the decrease in endothelial viability and reduces the release of lactate dehydrogenase (LDH) induced by high glucose. Vildagliptin potently suppresses high glucose-induced generation of reactive oxygen species (ROS) and production of vascular inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), intercellular cell adhesion molecule-1 (ICAM-1) and monocyte chemotactic protein 1 (MCP-1). Moreover, vildagliptin suppresses adhesion of monocytes to endothelial cells and induction of toll-like receptor 4 (TLR-4) in HAECs caused by high glucose. Mechanistically, we found that the cellular protective effects mediated by vildagliptin involve suppression of nuclear factor-kappa B (NF-κB) nuclear signals. Collectively, our data indicate that vildagliptin possesses a protective function in vascular cells.