Ten patients with high-risk acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS) relapsing early (< 1 year, n = 8) or late (> or = 1 year, n = 2) after allogeneic transplantation were treated with cytoreductive chemotherapy followed by unmanipulated peripheral blood stem cell transplantation (PBSCT) from related (n = 3) and unrelated donors (n = 7). In order to enhance the graft-versus-leukemia effect, patients received no graft-versus-host disease (GVHD) prophylaxis and granulocyte-macrophage colony-stimulating factor (GM-CSF) was given at a dose of 60 micrograms/m2 after transplant. Acute GVHD grade I-IV was seen in all patients. Eight out of ten patients achieved complete remission: one out of two patients with AML and late relapse is in good condition with limited chronic GVHD more than 1 year after the second PBSCT. The other patient died on day +171 after the second PBSCT from cerebral aspergillosis. One patient with blastic phase CML achieved molecular remission but died +330 days after the second PBSCT because of intracranial bleeding. Of the remaining five patients, three died of infectious complications on days +36, +70, and +27, one patient died with extramedullary relapse on day +35, and one from multi-organ failure in association with acute GVHD on day +32 after the second PBSCT. Two out of ten showed progressive disease and died on days +30 and +90, respectively. Although several patients achieved complete remission, the high risk of GVHD and treatment-related mortality should be kept in mind, especially when a second transplant is considered during a period of less than 12 months after the first procedure. Monitoring of minimal residual disease might predict relapse thus preventing high doses of cytotoxic drugs for reconditioning. The potential of GM-CSF to enhance the graft-versus-leukemia reactivity after cytoreductive therapy for allogeneic transplantation warrants further investigation.