Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of anti-diabetic compounds, are effective in treatment of hyperglycemia. Since atherosclerosis-related cardiovascular diseases are the major complications of diabetes, it is important to determine the effect of DPP-4 inhibitors on atherosclerosis. In this study, nondiabetic and diabetic apolipoprotein E (apoE)-deficient mice were treated with DPP-4 inhibitor alogliptin for 24 weeks and atherosclerotic lesions in aortic origins were examined. Results showed that diabetes significantly increased atherosclerotic lesions, but alogliptin treatment reduced atherosclerotic lesions in diabetic mice. Metabolic studies showed that diabetes increased plasma glucose and alogliptin treatment reduced glucose. Furthermore, immunohistochemistry study showed that diabetes increased IL-6 and IL-1β protein expression in atherosclerotic plaques, but alogliptin treatment attenuated diabetes-augmented IL-6 and IL-1β expression. In consistence with the observations from the mouse models, our in vitro studies showed that alogliptin inhibited toll-like receptor (TLR)4-mediated upregulation of IL-6, IL-1β, and other proinflammatory cytokines by mononuclear cells. Taken together, our findings showed that alogliptin inhibited atherosclerosis in diabetic apoE-deficient mice and the actions of alogliptin on both glucose and inflammation may contribute to the inhibition.