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The mechanism by which IFN-γ inhibits tumor cell growth has not been fully understood. Here we report that IFN-γ up-regulated the expression of Fas and Fas ligand (FasL) on HT29 cells, a human colon adenocarcinoma cell line, and subsequently induced apoptosis of these cells. The kinetics of cell death in IFN-γ-treated HT29 cells paralleled the increase in the levels of Fas and FasL expression. We further show that IFN-γ up-regulated the expression of Fas and FasL in STAT1-transfected U3A cells but not in STAT1-deficient U3A cells. Correspondingly, IFN-γ induced cell death in STAT1-transfected U3A cells but not in STAT1-deficient U3A cells. IFN-γ-induced cell death was inhibited by caspase-1 inhibitors. Our results suggest that cell growth inhibition by IFN-γ is due to apoptosis mediated by Fas and FasL interaction.