Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features^{, –}. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens. We therefore isolated a high-affinity Wilms’ Tumor Antigen 1-specific TCR (TCR_C4) from HLA-A2⁺ normal donor repertoires, inserted TCR_C4 into Epstein–Bar virus-specific donor CD8⁺ T cells (T_TCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival^,, and infused these cells prophylactically post-HCT into 12 patients (NCT01640301). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). T_TCR-C4 maintained TCR_C4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.