Background : Hyperhomocysteinemia(HHcy) is an independent risk factor for atherosclerosis. In recent years, endoplasmic reticulum(ER) stress has been proposed to explain the cellular mechanisms by which HHcy promotes cardiovascular disease and also HHcy can increase S-adenosylhomocysteine (SAH), a potent methyltransferase inhibitor which has been known to inhibit Ras/MAPK pathway and Akt signaling. TRAIL is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis upon binding to its receptors. The macrophage which is important cell in the atherosclerotic plaque,rapidly express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) after activation with interferon(IFN)-gamma which also known to be abundant in atherosclerotic plaque. The cytotoxic activity of TRAIL is relatively selective to cancer cells compared to normal cells which has decoy receptor(DcR1 and DcR2). Endothelial cells express TRAIL receptors but the function of TRAIL in endothelial cells is not completely understood. So we performed the study to determine whether homocysteine could increase TRAIL expression in macrophage and modulate TRAIL mediated endothelial cytotoxicity,if so,the underlyng mechanism. Methods and Results : First,we found that SAH significantly increases TRAIL expression in THP-1 monocytes. These effects were primarily mediated by activation of FOXO3a. Second,the expression of TRAIL death receptor (DR4,DR5) in endothelial cell(HUVEC) was significantly increased by homocysteine,whereas the decoy receptor(DcR1,DcR2) was significantly decreased. Third,we determined that whether homocysteine modulates TRAIL activity in HUVECs. We examined apoptosis in endothelial cell with soluble form TRAIL. The TRAIL significantly induced apoptosis in SAH-pretreated HUVECs. In co-culture of THP-1 and HUVECs, homocysteine increases TRAIL-mediated Endotheial Apoptosis. Conclusions : We concluded that TRAIL mediated endothelial apoptosis would be a new mechanism of in atherosclerosis in HHy.