A subpopulation of T cells that express CD161⁺CD95⁺CD45RA^–CD127^hCD28⁺CD25^int are prepared to survive chemotherapy through rapid efflux of toxins and to maintain host protection with a Th1 proinflammatory profile and high expansion potential. This memory T-cell subpopulation is resistant to chemotherapy because of selective expression of the multidrug transporter MDR1. They are quiescent but are capable of self-renewal and proliferation and can differentiate into other cell subsets. These cells express stem-cell–associated markers (c-kit), lack exhaustion markers such as CD57, and display relative quiescence with low Ki-67 expression. This particular subset of memory T cells might play a crucial role for immune reconstitution upon chemotherapy-induced lymphopenia, could be relevant for T-cell memory maintenance under normal conditions, and would be an attractive population for T-cell immunotherapy.