Tumor necrosis factor-alpha (TNF alpha) mediates cytochrome c release from mitochondria, loss of mitochondrial membrane potential (Delta Psim) and apoptosis in sensitive leukemic cells. In the present study, by using the human leukemic U937 cell line, we demonstrate that the cytochrome c release is caspase-8-dependent and can be blocked by an inhibitor of caspase-8, Z-Ile-Glu (OMe)-Thr-Asp(OMe)-fluoromethyl ketone (Z-IETD.fmk), or a pan caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD.fmk). However, TNF alpha -mediated loss of Delta Psim was not inhibited by caspase inhibitors. The apoptotic process was blocked by either Z-IETD.fmk or Z-VAD.fmk in cells with lower Delta Psim. U937 cells with stable transfection of the cellular inhibitor of apoptosis protein 1 (c-IAP1) are resistant to TNF alpha -induced activation of caspases, Bid cleavage, cytochrome c release and Delta Psim collapse. In addition, both c-IAP1 and XIAP were not up-regulated upon prolonged exposure to TNF alpha. In contrast, there was a caspase-dependent cleavage of XIAP, but not c-IAP1, during treatment with TNF alpha for 7 days. These results demonstrate that c-IAP1 blocks TNF alpha signaling at a level controlling both activation of caspase-8 and a signal to cause loss of Delta Psim. The sensitive U937 cell line failed to acquire resistance and gain a self-protecting advantage against apoptosis, upon induction of c-IAP1 expression.