Apoptosis is a critical regulator of homeostasis in the immune system. In this study we demonstrate that memory CD8+ T cells are more resistant to apoptosis than naive cells. After whole body irradiation of mice, both naive and memory CD8+ T cells decreased in number, but the reduction in the number of naive cells was 8-fold greater than that in memory CD8+ T cells. In addition to examining radiation-induced apoptosis, we analyzed the expansion and contraction of naive and memory CD8+ T cells in vivo following exposure to Ag. We found that memory CD8+ T cells not only responded more quickly than naive cells after viral infection, but that secondary effector cells generated from memory cells underwent much less contraction compared with primary effectors generated from naive cells (3-to 5-fold vs 10-to 20-fold decrease). Increased numbers of secondary memory cells were observed in both lymphoid and non-lymphoid tissues. When naive and memory cells were transferred into the same animal, secondary effectors underwent less contraction than primary effector cells. These experiments analyzing apoptosis of primary and secondary effectors in the same animal show unequivocally that decreased downsizing of the secondary response reflects an intrinsic property of the memory T cells and is not simply due to environmental effects. These findings have implications for designing prime/boost vaccine strategies and also for optimizing immunotherapeutic regimens for treatment of chronic infections.