Epidermal growth factor (EGF) protects against death receptor induced apoptosis in epithelial cells. Herein, we demonstrate that EGF protection against tumor necrosis factor related apoptosis‐inducing ligand (TRAIL) induced apoptosis is mediated by increased expression of the Bcl‐2 family member myeloid cell leukemia 1 (Mcl‐1). EGF increased the mRNA and protein levels of Mcl‐1. Furthermore, expression of ErbB1 alone or in combination with ErbB2 in NIH3T3 cells up‐regulates Mcl‐1 following EGF treatment. In addition, up‐regulation of Mcl‐1 by EGF is mediated through AKT and NFκB activation since kinase inactive AKT and ΔIκB effectively blocks this up‐regulation. NFκB was also critical for the ability of EGF to prevent TRAIL induced apoptosis as a dominant negative IκB (ΔIκB) blocked NFκB activation, and relieved EGF protection against TRAIL mediated mitochondrial cytochrome‐c release and apoptosis. Finally, anti‐sense oligonucleotides directed against Mcl‐1 effectively reduced the protein levels of Mcl‐1 and blocked EGF protection against TRAIL induced mitochondrial cytochrome‐c release and apoptosis. Taken together, EGF signaling leads to increased Mcl‐1 expression that is required for blockage of TRAIL induced apoptosis. © 2003 Wiley‐Liss, Inc.