We have investigated the susceptibility of mouse T cells at various maturation and activation stages to recombinant soluble mouse Fas ligand (termed WX1). CD4+CD8+ thymocytes were preferentially killed by WX1, although CD4+CD8- and CD4-CD8+ thymocytes were also killed at higher concentrations of WX1. The majority of CD4-CD8- thymocytes were resistant to the same doses of WX1. Naive peripheral T cells were also killed by WX1 at concentrations similar to those for single-positive thymocytes. Activation-induced cell death of previously activated T cells is known to be mediated by Fas and Fas ligand. However, the activation of naive splenic T cells by mAbs against CD3/TCR complex rather induced resistance against WX1. This resistance was induced in activated T cells but not in bystander T cells. These mechanisms seem to explain why activated T cells are not immediately killed and why bystander T cells are not activated in an Ag-nonspecific manner.