This study aimed to elucidate whether the effect of cilostazol to suppress apoptotic cell death is directly coupled to cAMP-dependent protein kinase activation in human umbilical vein endothelial cells (HUVECs). After exposure of HUVECs to LPS (1μgml −1 ) for 18h, the endothelial cells irregularly aggregated with loss of cobblestone appearance, which was reversed by cilostazol (1–100μM), as well as by cilostamide (cilostazol analog), and cilostazol metabolites (OPC-13015 and OPC-31213), respectively. LPS-stimulated production of reactive oxygen species (ROS) was significantly reduced by cilostazol (0.1–10μM). In line with these, LPS (1μgml −1 )- and TNF-α (200ngml −1 )-induced DNA fragmentation, assessed by agarose gel electrophoresis, was significantly reduced by treatment with cilostazol (10μM) as well as by dibutyryl cAMP (100μM). This effect was reversed by cAMP-dependent protein kinase inhibitor, Rp-cAMPs (200μM). Further, LPS (1μgml −1 )-induced decrease in Bcl-2 and increase in Bax protein expression were fully reversed by cilostazol (10μM) and dibutyryl cAMP (100μM), all of which were antagonized by Rp-cAMPs (200μM). Taken together, cilostazol effectively protected HUVECs from LPS- and TNF-α-induced cell death associated with oligonucleosomal DNA fragmentation via activation of cAMP-dependent protein kinase.