Fas ligand (fasL) transgenic (Tg) mice were produced by introducing a murine fasL cDNA under the control of a TCR β-chain enhancer minigene. Higher levels of fasL expression with increased biologic activity were observed in the Tg mice compared with non-Tg mice. Numbers of CD4+CD8+ T cells in the thymus and T cells in the lymph node and spleen were lower in the fasL Tg mice compared with the non-Tg mice. This is consistent with a reduction in the size of the T cell areas in fasL Tg mice compared with non-Tg mice. Conversely, in fasL Tg mice, there was an increase in the number and size of apoptotic foci associated with phagocytic cells, as determined by in vivo TUNEL (TdT-mediated dUTP nick-end labeling) staining. Stimulation of non-Tg mice in vivo with anti-CD3 Ab for 3 days resulted in greatly increased apoptosis of CD4+CD8+ thymocytes and lymph node T cells. Surviving thymocytes and T cells of lymph node and spleen expressed Fas at low levels. After similar stimulation of fasL Tg mice, however, a discreet population of surviving cells expressed high levels of Fas, indicating that a novel population of Fas apoptosis-resistant cells develops in these mice. These results indicate that high levels of fasL can result in both increased Fas-mediated apoptosis and the development of T cells that express high levels of Fas, but are resistant to Fas-mediated apoptosis.