Abstract Epithelial cell apoptosis triggered cooperatively by multiple cytokines contributes to the injury induced by inflammatory responses in the lung and elsewhere. Here we show that interferon-γ (IFN-γ) sensitizes A549 cells, human lung epithelial cells, to cytokine-mediated apoptosis by upregulating caspase-8 expression. Pretreating the cells with IFN-γ potentiated Fas- and TNF-related apoptosis inducing ligand (TRAIL)-induced cell death, but other forms of apoptosis, not mediated via receptors, were unaffected. Western blotting and inhibitor assays showed that IFN-γ selectively increased expression of caspases-7 and -8, but not caspases-2, -3, -9, or -10, as a necessary step leading to apoptosis. Assaying promoter activity using a luciferase reporter gene indicated that an IFN-γ response element was located in the 5′-flanking region of the caspase-8 gene, spanning positions -227 to -219. Taken together, these findings suggest that IFN-γ potentiates Fas- and TRAIL-mediated apoptosis by increasing caspase-8 expression via an IFN-γ response element in A549 cells.