The tumor necrosis factor (TNF) is a cytokine known to be an important mediator of apoptosis and inflammation. It has been implicated in the pathogenesis of a number of diseases, including cancer and rheumatoid arthritis. TNF apoptosis has been known for a number of years to be critically dependent on caspases; however, recently it has been suggested that cysteine cathepsins might also be involved in the pathway. In the present work the hypothesis that cathepsins can act as an essential downstream mediator of TNF-alpha-triggered apoptosis was tested. The TNF-alpha apoptosis was investigated in two tumor-cell lines: U937 and T98G. Based on the use of pharmacological caspase inhibitors, the TNF-alpha induced caspase-dependent apoptotic cell death in both cell lines, which was accompanied by lysosomal destabilization and the release of cathepsins in the cytosol. However, blocking cysteine cathepsins with a broad-spectrum inhibitor, E64d, or a more specific cathepsin B inhibitor, CA-074Me, had no effect on the progression of the apoptosis in both cell lines, suggesting that the TNF-alpha apoptosis is not critically dependent on the cathepsins in these two cellular models.