Tumor necrosis factor (TNF)α is considered to play a key pathogenetic role in inflammatory bowel diseases. In this study we analyzed the mechanisms by which TNFα induces intestinal epithelial cell apoptosis. TNFα alone, and more potently in combination with IFNγ, induced a high degree of IEC-6 cell apoptosis. This effect was more than 100-fold stronger if both of the TNF-R were stimulated, compared to stimulation of the p55-TNF-R alone, indicating an important apoptosis enhancing effect of the p75-TNF-R. TNFα-induced apoptosis required activation of ICE caspases and was completely abolished by its inhibitor, zVAD-fmk. Specific inhibition of caspase-3 with zDEVD-fmk did not alter the effect of TNFα. Western blot analyses confirmed that caspase-3 was not activated in response to TNFα. In the presence of complete inhibition of the caspase cascade with zVAD-fmk (≥50 μM), TNFα induced cell necrosis rather than apoptosis. Our data reveal that TNFα can trigger enterocyte cell death via apoptosis or necrosis, depending upon the activation or blockade of specific caspases.