The major cause of failure after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) is disease relapse or progression. We analyzed the outcome of second HSCT for treatment of patients with relapsed, refractory AML/myelodysplastic syndrome (MDS) at our institution. A total of 72 patients were eligible for this analysis. In all, 25 (35%) patients received salvage chemotherapy prior to the second transplant procedure and only two (3%) patients were in complete remission at the time of the second transplant. A total of 20 patients (28%) had low leukemia burden as measured by the absence of peripheral blood blasts and <or=5% blasts in the bone marrow at the time of the second transplant. Although, the overall median survival after the second transplant was 6 months, a subset of patients who had low leukemia burden at the time of the second transplant had a 5-year survival of 25 vs 12% in those with a high leukemia burden. Thus, a second transplant may offer the possibility of long-term disease control in a subset of patients who have a 'low bulk' disease at the time of transplantation.