Several cysteine and serine protease inhibitors previously shown to block TCR-induced death of 2B4 T hybridoma cells were tested for their ability to block various T lymphocyte apoptotic death systems. TCR-induced death of both peripheral CD4+ and CD8+ T cell blasts was inhibited similarly to the hybridoma, but cell death in these cells induced by anti-Fas, gamma-irradiation, etoposide, or extracellular ATP was not blocked. For T cell lines, cell death induced by CTL or by IL-2 withdrawal was also not inhibited. TCR-induced death of immature CD+8+ thymocytes triggered by culture on immobilized anti-CD3 was not blocked by these protease inhibitors, whereas similar death induced in the resting CD4+8- thymocyte subset under these conditions was inhibited similarly to the T cell blasts. TCR-induced proliferation of the latter subset was modest in the absence of exogeneous IL-2, but was enhanced two- to fourfold by the protease inhibitors. These results show that a protease-dependent death pathway can be triggered by the TCR in mature T cells; similar protease-dependent steps are not common to the TCR-triggered activation pathway or other apoptotic death pathways in these cells.