The primary objective of this clinical trial was to evaluate the safety, feasibility, and biologic effects of administering costimulated, interleukin (IL)-4 polarized donor CD4⁺ T cells in the setting of HLA-matched sibling, T cell-replete allogeneic hematopoietic cell transplantation (HCT). Forty-seven subjects with hematologic malignancy received granulocyte colony-stimulating factor-mobilized allogeneic hematopoietic cell transplants and cyclosporine graft-versus-host disease (GVHD) prophylaxis after reduced intensity conditioning. Initial subjects received no additional cells (n = 19); subsequent subjects received additional donor CD4⁺ T cells generated ex vivo by CD3/CD28 costimulation in medium containing IL-4 and IL-2 (administered day 1 after HCT at 5, 25, or 125 × 10⁶ cells/kg). Studies after HCT included measurement of monocyte IL-1α and tumor necrosis factor α, detection of T cells with antitumor specificity, and characterization of T cell cytokine phenotype. The culture method generated donor CD4⁺ T cells that secreted increased T helper 2 (Th2) cytokines and decreased T helper 1 (Th1) cytokines. Such Th2-like cells were administered without infusional or dose-limiting toxicity. The Th2 cohort had accelerated lymphocyte reconstitution; both cohorts had rapid hematopoietic recovery and alloengraftment. Acute GVHD and overall survival were similar in the Th2 and non-Th2 cohorts. Th2 cell recipients tended to have increased monocyte IL-1α and had increased tumor necrosis factor α secretion. CD8⁺ T cells with antitumor specificity were observed in Th2 and non-Th2 cohorts. Post-transplantation T cells from Th2 cell recipients secreted IL-4 and IL-10 (Th2 cytokines) and IL-2 and interferon γ (Th1 cytokines). Allograft augmentation with costimulated, IL-4-polarized donor CD4⁺ T cells resulted in activated Th1, Th2, and inflammatory cytokine pathways without an apparent increase in GVHD.