Ectopic expression of Bcr-Abl, Bcl-2 or Bcl-x(L) in HL-60 cells conferred resistance to apoptosis against a variety of death-inducing agents. Bcr-Abl-mediated interference with mitochondrial events was confirmed by the analysis of the loss of mitochondrial transmembrane potential and cytochrome c release. HL-60.Bcr-Abl cells were extremely resistant to all apoptogenic stimuli tested, even in circumstances where HL-60.Bcl-2 or HL-60.Bcl-x(L) cells were only partially protected from apoptosis. The levels of Mcl-1, Bax, Bid, Akt, c-IAP-1, c-IAP-2, XIAP and c-FLIP were compared in all HL-60 lines. Our findings show that Bcr-Abl is a more powerful anti-apoptotic molecule than Bcl-2 or Bcl-x(L).