Tumor necrosis factor alpha (TNF-a) is one of the best-described cell death promoters. In murine L929 fibroblasts, dexamethasone inhibits TNF-a-induced cytotoxicity. Since phosphatidyl inositol 3 kinase (PI3K) and nuclear factor kappa B (NF-jB) proteins regulate several survival pathways, we evaluated their participation in dexamethasone protection against TNF-a cell death. We interfered with these pathways by overexpressing a negative dominant mutant of PI3K or a non-degradable mutant of inhibitor of NF-jB alpha (IjBa) (the cytoplasmic inhibitor of NF-jB) in L929 cells. The mutant IjB, but not the mutant PI3K, abrogated dexamethasone-mediated protection. The loss of dexamethasone protection was associated with a diminished accumulation in XIAP and c-IAP proteins.