Histone deacetylase inhibitors such as Vorinostat display anti-neoplastic activity against avariety of solid tumors. Here, we have investigated the anti-tumoral activity of Vorinostaton endometrial cancer cells. We have found that Vorinostat caused cell growth arrest, lossof clonogenic growth and apoptosis of endometrial cancer cells. Vorinostat-induced theactivation of caspase-8 and -9, the initiators caspases of the extrinsic and the intrinsicapoptotic pathways, respectively. Next, we investigated the role of the extrinsic pathwayin apoptosis triggered by Vorinostat. We found that Vorinostat caused a dramatic decreaseof FLIP mRNA and protein levels. However, overexpression of the long from of FLIP did notblock Vorinostat-induced apoptosis. To further investigate the role of extrinsic apoptoticpathway in Vorinostat-induced apoptosis, we performed an shRNA-mediated knock-down of caspase-8. Surprisingly, downregulation of caspase-8 alone caused a markeddecrease in clonogenic ability and reduced the growth of endometrial cancer xenograftsin vivo, revealing that targeting caspase-8 may be an attractive target for anticancer ther-apy on endometrial tumors. Furthermore, combination of caspase-8 inhibition and Vorino-stat treatment caused an enhancement of apoptotic cell death and a further decrease ofclonogenic growth of endometrial cancer cells. More importantly, combination of Vorino-stat and caspase-8 inhibition caused a nearly complete inhibition of tumor xenograftgrowth. Finally, we demonstrate that cell death triggered by Vorinostat alone or incombination with caspase-8 shRNAs was inhibited by the anti-apoptotic protein Bcl-XL.Our results suggest that combinatory therapies using Vorinostat treatment and caspase-8 inhibition can be an effective treatment for endometrial carcinomas.