Allogeneic stem-cell transplantation (SCT) is potentially curative treatment for AML and MDS. New conditioning regimens are continuously explored trying to reduce toxicity while maintaining antileukemia effect. Treosulfan is an alkylating agent with in vitro cytotoxicity against leukemia as well as myeloablative and immunosuppressive properties when used in escalated doses. We explored a regimen of fludarabine (30 mg/m(2) x 5) and treosulfan (12 gr/m(2) x 3) in 24 patients, median age 55 years (range, 30-69), with AML (n = 19) or MDS (n = 5), not eligible for standard myeloablation. Donors were HLA-matched siblings (n = 11) or matched-unrelated (n = 13). Twenty-one patients engrafted within a median of 15 days. Extramedullary toxicity was relatively limited. The incidence of acute and chronic GVHD was 15% and 47%, respectively. With median follow-up of 19 months (range, 8 - 34), 16 patients are alive and 8 died (relapse-2, treatment-related-6). Two-year disease-free survival rate was 60% (95% CI, 39-81). The cumulative incidence of relapse was only 15% (95% CI, 5 - 44) while nonrelapse mortality rate was 25% (95% CI, 13-50). The fludarabine/treosulfan regimen can be considered a fully intensive, modified myeloablative regimen with effective antileukemia activity and acceptable toxicity in patients with AML/MDS not eligible for standard myeloablation, and merits further study in larger scale studies.