Amphibian metamorphosis induced by thyroid hormone (T₃) involves programmed cell death and the differentiation of various types of cells in degenerated and reconstructed tissues. However, the signaling pathway that directs the T₃-dependent cell-fate determinations remains unclear. Tumor necrosis factor- (TNF-) is a pleiotropic cytokine that affects diverse cellular responses. Engagement of TNF- with its receptor (TNFR1) causes intracellular apoptotic and/or survival signaling. To investigate TNF signaling functions during anuran metamorphosis, we first identified Xenopus laevis orthologues of TNF- (xTNF-) and its receptor (xTNFR1). We found that xTNF- activated nuclear factor B (NF-B) in X. laevis A6 cells through the Fas-associated death domain (xFADD) and receptor-interacting protein 1 (xRIP1). Interestingly, xTNF- mRNA in blood cells showed prominent expression at prometamorphosis during metamorphosis. Next, to elucidate the apoptotic and/or survival signaling induced by xTNF- in an in-vitro model of metamorphosis, we established a vascular endothelial cell line, XLgoo, from X. laevis tadpole tail. XLgoo cells formed actin stress fibers and elongated in response to xTNF-. T₃ induced apoptosis in these cells, but the addition of xTNF- blocked the T₃-induced apoptosis. In addition, treatment of the cells with T₃ for 2 days induced the expression of thyroid hormone receptor (TR) and caspase3, and this TR induction was drastically repressed by xTNF-. Furthermore, in organ culture of the tail, xTNF- significantly attenuated the tail degeneration induced by T₃. These findings suggested that xTNF- could protect vascular endothelial cells from apoptotic cell death induced by T₃ during metamorphosis, and thereby participate in the regulation of cell fate.