Abstract It is uncertain whether NK cells modulate T cell memory differentiation. By using a genetic model that allows the selective depletion of NK cells, we show in this study that NK cells shape CD8+ T cell fate by killing recently activated CD8+ T cells in an NKG2D- and perforin-dependent manner. In the absence of NK cells, the differentiation of CD8+ T cells is strongly biased toward a central memory T cell phenotype. Although, on a per-cell basis, memory CD8+ T cells generated in the presence or the absence of NK cells have similar functional features and recall capabilities, NK cell deletion resulted in a significantly higher number of memory Ag-specific CD8+ T cells, leading to more effective control of tumors carrying model Ags. The enhanced memory responses induced by the transient deletion of NK cells may provide a rational basis for the design of new vaccination strategies.