Relapsed acute leukemia after allogeneic transplantation has a poor prognosis and most reports have focused on the role of second transplantations in relapsed patients. We report our single-institution experience on the management of relapsed acute leukemia after allogeneic transplantation. We aimed to describe the outcome of relapsed acute leukemia after allogeneic transplantation at our institution and investigate whether maneuvers intended to augment donor T cell allogeneic reactivity were associated with durable graft-versus-leukemia effects. We analyzed 310 patients with acute leukemia who received allogeneic hematopoietic progenitor cell transplants from HLA-matched donors between 1982 and 2005 (229 with acute myelogenous leukemia, 81 with acute lymphoblastic leukemia). Mean post-transplant follow-up was 5 years (range, 0.5-22 years). Factors associated with relapse incidence, therapy for relapse, response to treatment, and post-relapse survival were assessed. One hundred of 310 patients (32%) with acute leukemia relapsed after transplantation, including 28 of 81 patients (35%) with acute lymphoblastic leukemia and 72 of 229 (31%) with acute myelogenous leukemia at a median of 136 days after transplantation. Median post-relapse survival periods were 51 days for the 69 patients who received chemotherapy/supportive care, 84 days for 11 recipients of donor lymphocyte infusions, 303 days for 13 recipients of second transplants, and 442 days for 7 patients treated with interferon-alpha and granulocyte-macrophage colony-stimulating factor. A multivariable Cox regression analysis indicated that a longer time to relapse after transplantation, peripheral blood as source of stem cells, and initial post-relapse therapy with cytokines, donor lymphocyte infusions, or second transplants were associated with improved post-relapse survival (P <.001, <.001, and .025). The outlook for patients with post-transplant relapse of acute leukemia is extremely poor; currently, no single therapy consistently results in durable remissions. Our study highlights the need for clinical trials in this area. Therapy with granulocyte-macrophage colony stimulating factor and interferon-alpha-2b is promising and will be pursued in a prospective trial at our center.