Transplant-related problems have been partially overcome by using reduced-intensity conditioning (RIC), graft engineering, and alternative donors. In all, 21 leukemia patients with no suitable donor received a hematopoietic stem cell transplantation from a mismatched/haploidentical related (n=16) or unrelated donor (n=5). Fludarabine-RIC and PBSC graft were used. Manipulation was done by CD34+ selection (n=9) or CD3/CD19 depletion (n=12). Results were compared with patients (n=26) conditioned with the same regimen and grafted with a CD34+-selected PBSC from identical related donors. Median time to neutrophil recovery was 12 days (range, 10-19 d). Platelet engraftment was faster with a CD3/CD19-depleted graft (median, 11 d; range, 9-21) than with a CD34+ graft (median, 14 d; range, 9-53; P=0.003). Full donor chimerism in bone marrow CD34+ cells was higher in CD3/CD19-depleted graft group compared with CD34+-selected group (P=0.02). CD3/CD19 depletion showed higher natural killer cell counts even after 1 year. Nonrelapse mortality (7% for matched CD34+-selected grafts and 11% for mismatched/haplo-CD3/CD19-depleted grafts), relapse probability (27% for related CD34+-selected patients and 33% for related CD3/CD19-depleted patients), and disease-free survival were similar for both the groups. In conclusion, using graft engineering procedures after RIC for hematopoietic stem cell transplantation offers a high probability of engraftment, fast immune recovery, and very low mortality even with mismatched donors.