In human monocytes, tumor necrosis factor (TNF) induces a proinflammatory response. In NF-?B–inhibited monocytes, TNF stimulates cell death/apoptosis. In the present study, we analyzed the response of acute myeloid leukemia (AML) cells to TNF stimulation in conjunction with NF-?B inhibition. In all AML-derived cells tested, NF-?B–inhibited cells were resistant to TNF-induced apoptosis. Further investigation revealed that the cytoprotective gene heme oxygenase-1 (HO-1) was induced in NF-?B–inhibited AML cells in response to TNF stimulation, and HO-1 was responsible for the resistance of AML cells to the cytotoxic actions of TNF. Moreover, after transfection with HO-1 siRNA, the resistance to TNF-induced cell death signals of AML cells was removed. The HO-1 promoter region contains antioxidant-response elements that can bind the transcription factor NF-E2–related factor 2 (Nrf2). We further demonstrated that Nrf2 was activated by TNF under NF-?B–inhibited conditions, to play the major role in up-regulating HO-1 expression and ultimately the fate of AML cells. These results demonstrate a novel mechanism by which TNF-induced cell death is inhibited in AML cells through the induction of HO-1, via Nrf2 activation.