Donor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti–interleukin-2 (IL-2) monoclonal antibody (JES6-1) forms anti–IL-2/IL-2 complexes that block IL-2 binding to IL-2Rβ and IL-2Rγ on conventional T cells that have low expression of IL-2Rα. Here, we show that administration of JES6 early after allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti–IL-2 treatment downregulated activation of the IL-2-Stat5 pathway and reduced production of granulocyte-macrophage colony-stimulating factor (GM-CSF). In GVHD target tissues, enhanced T-cell programmed cell death protein 1 (PD-1) interaction with tissue–programmed cell death-ligand 1 (PD-L1) led to reduced activation of protein kinase–mammalian target of rapamycin pathway and increased expression of eomesodermin and B-lymphocyte-induced maturation protein-1, increased T-cell anergy/exhaustion, expansion of Foxp3^–IL-10–producing type 1 regulatory (Tr1) cells, and depletion of GM-CSF–producing T helper type 1 (Th1)/cytotoxic T cell type 1 (Tc1) cells. In recipient lymphoid tissues, lack of donor T-cell PD-1 interaction with tissue PD-L1 preserved donor PD-1⁺TCF-1⁺Ly108⁺CD8⁺ T memory progenitors and functional effectors that have strong GVL activity. Anti–IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8⁺ T memory progenitor cells are enriched with anti–IL-2 treatment compared with TAC treatment. We conclude that administration of tolerogenic anti–IL-2 monoclonal antibody early after allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.