IFN-γ regulates multiple processes in the immune system. Although its antimicrobial effector functions are well described, less is known about the mechanisms by which IFN-γ regulates CD8+ T cell homeostasis. With the help of adoptive T cell transfers, we show in this study that IFN-γR signaling in CD8+ T cells is dispensable for expansion, contraction, and memory differentiation in response to peptide vaccination. In contrast, host IFN-γR signaling counterregulates CD8+ T cell responses and the generation of effector memory T cell processes, which are partially regulated by CD11b+ cells. Similar to vaccination-induced proliferation, host IFN-γR signaling limits the expansion of naive CD8+ T cells and their differentiation into effector memory-like T cells in lymphopenic mice. In contrast to peptide vaccination, IFN-γR signaling in CD8+ T cells contributes to memory fate decision in response to lymphopenia, an effect that is fully reversed by high-affinity TCR ligands. In conclusion, we show that host IFN-γR signaling controls the magnitude of CD8+ T cell responses and subsequent memory differentiation under lymphopenic and nonlymphopenic conditions. In contrast, IFN-γR signaling in CD8+ T cells does not affect cell numbers under either condition, but it directs memory fate decision in response to weak TCR ligands.