Endometrial carcinomas are often chemoresistant. TNF shows potent antitumour activity against various cancers, and if it demonstrates good antitumour activity against endometrial cancer, the cytokine could represent a valuable alternative therapeutic approach. We have tested the ability of TNF to induce apoptosis in endometrial carcinoma cells, and examined a putative role for XIAP in regulating cellular sensitivity to the cytokine. Exposure to TNF triggered TNF-R1-dependent activation of caspases-8, -9 and -3, downregulated Akt and XIAP proteins and induced dose-dependent and time-dependent apoptosis in Ishikawa cells. On the opposite, TNF upregulated XIAP in Hec-1A cells; in these cells, the cytokine induced delayed TNF-R1-dependent activation of caspase-8, and failed to activate caspases -9 and -3 and to induce apoptotsis. However, XIAP siRNA restored TNF-induced caspase signaling and apoptosis in Hec-1A cells; XIAP siRNA also increased TNF-induced apoptosis in Ishikawa cells. In addition, inhibition of PKC activity enhanced TNF-induced downregulation of XIAP and potentiated apoptosis induction, in both Ishikawa and Hec-1A cells. Finally, we found XIAP immunoreactivity in epithelial cells from a large number of human endometrial tumor tissue samples, indicating that XIAP is produced by endometrial tumor cells in vivo. This could allow XIAP to play a putative in vivo role in counteracting TNF-induced apoptosis in endometrial tumor cells; in this case, direct or indirect targeting of XIAP should potentiate the antitumor effect of TNF.