Viruses can cause a severe lymphopenia early in infection and a subsequent, lasting loss of pre-existing CD8(+) memory T cells. We therefore questioned how well virus Ag-specific memory CD8(+) T cells could reconstitute mice rendered lymphopenic as a consequence of genetics, irradiation, or viral or poly(I:C)-induced cytokines. In each case, reconstitution of the CD8(+) compartment was associated with limited division of virus-specific memory T cells and a reduction in their proportion. This indicates that foreign Ag-experienced CD44(high)CD8(+) memory T cells may respond differently to homeostatic signals than other CD44(high)CD8(+) cells, and that events inducing lymphopenia may lead to a permanent reduction in T cell memory.