Moderate alcohol consumption has been shown to reduce atherosclerosis-associated diseases. As shown in our earlier works, ethanol has a dose-dependent protective effects against endothelial cellular senescence by activating aldehyde dehydrogenase 2 (ALDH2) in vitro. However, whether ethanol administration possesses anti-atherosclerosis properties and whether ALDH2 is involved in the underlying mechanisms are unknown. In the present study, we revealed that the appropriate dose of ethanol reduced atherosclerotic plaque formation, and upregulated ALDH2 expression and activity in ApoE(-/-) mice. ALDH2 deficiency blocked the protection of ethanol against atherosclerotic plaque formation by inhibiting endothelium senescence. In contrast, Alda-1, which is a specific enzymatic agonist of ALDH2, enhanced the anti-senescence and anti-atherosclerosis effects of the appropriate dose of ethanol. Furthermore, following ALDH2 knockdown, resveratrol (an anti-aging compound) recovered the beneficial effects of ethanol against endothelial senescence in vitro. Thus, these results suggest that the appropriate dose of ethanol has protective effects against endothelial senescence and atherosclerosis by activating ALDH2. (C) 2019 Elsevier Inc. All rights reserved.