The mechanisms that maintain human T cell memory during normal and perturbed homeostasis are not fully understood. The repeated induction of profound lymphocytopenia in patients undergoing multiple cycles of cytotoxic chemotherapy infrequently results in severe infections with viruses controlled by memory T cells, suggesting that some memory T cells survive chemotherapy and restore immunity. Here, we identified a distinct subpopulation of memory CD8⁺ T cells with the ability to rapidly efflux and survive exposure to chemotherapy drugs in vitro and in vivo. T cells with high efflux capacity shared expression of molecules with hematopoietic stem cells, were quiescent in nonlymphocytopenic individuals, and were induced to proliferate in patients rendered lymphocytopenic after chemotherapy. Effluxing T cells differentiated into noneffluxing subsets in response to antigen stimulation and inflammatory signals, thereby contributing to repopulation of memory cells after chemotherapy.