Background: Homocysteine has been known to induce endothelial cell dysfunction. Recently, homocysteine was found to induce chemotactic factor and adhesion molecules, suggesting its role in leukocyte chemotaxis. Since homocysteine is found increased around damaged cells, if homocysteine induces chemotaxis, it might help clearing damaged cells by leukocyte. We hypothesized that physiologic high doses of homocysteine induced chemotaxis thus increased death-receptor mediated apoptosis in endothelial cells as well as damaged cells such as cancer cells. Methods: S-adenostlhomocysteine (SAH), a stable form of homocysteine, was induced intracellularly by administering homocystine(100uM), adenosine(50uM), and erythro-9-(2-hydroxy-3-nonyl) adenine(5uM) to the culture media and HUVECs were incubated for 24-48 hours. TRAIL receptor expression was measured by RT-PCR and western blots. To evaluate apoptosis sensitivity of HUVEC after SAH induction, cells were treated with soluble TRAIL for 24 hours. Results: 1) Intracellular SAH induction was found to reduce survival and proliferation of HUVEC by apoptosis evaluated by FACS for hypodiploid nuclei in 24 hours. 2) SAH induction was found to induce TRAIL receptors (DR4 and DR5) expression and to suppress TRAIL decoy receptors (DcR1 and DcR2) in HUVECs. Moreover, Soluble TRAIL increased apoptosis of HUVEC in SAH induced group. Induction of death receptors by SAH was suggested to mediate by Ras and Akt inhibition, because soluble TRAIL induced HUVEC apoptosis was reversed by co-transfection of Ad-myr Akt. 3) Finally, we found SAH induction in 6 gastric cancer cell lines increased adhesion of monocytes to cancer cells, increasing apoptosis of tumor cells. Conclusions: In this study, we found that SAH induces endothelial cell apoptosis by inducing death receptor expression via Akt and ERK pathway inhibition, which increase endothelial cell susceptibility to death ligand-mediated apoptosis. Moreover, we also found that SAH induction in cancer cells also increased death receptor mediated apoptosis. The finding of this study suggests role of homocysteine as a chemotatic molecule inducing clearance of damaged cells by leukocytes.