The role of reduced-intensity conditioning (RIC) regimens in pediatric cancer treatment is unclear. To define the efficacy of a busulfan/fludarabine/antithymocyte globulin RIC regimen in pediatric patients ineligible for myeloablative transplantation, we completed a trial at 23 institutions in the Pediatric Blood and Marrow Transplant Consortium. Forty-seven patients with hematologic malignancies were enrolled. Sustained engraftment occurred in 98%, 89%, and 90%, and full donor chimerism was achieved in 88%, 76%, and 78% of evaluable related bone marrow/peripheral blood stem cells (BM/PBSCs), unrelated BM/PBSCs, and unrelated cord blood recipients. With a median follow-up of 24 months (range, 11-53 months), 2-year event-free survival, overall survival (OS), transplantation-related mortality, and relapse were 40%, 45%, 11%, and 43%, respectively. Univariate analysis revealed an inferior outcome when patients had undergone previous total body irradiation (TBI)-containing myeloablative transplantation (2-year OS, 23% vs 63% vs 52%, previous TBI transplantation vs no TBI transplantation vs no transplantation, P = .02) and when patients not previously treated with TBI had detectable disease at the time of the RIC procedure (2-year OS, 0% vs 63%, detectable vs nondetectable disease, P = .01). Favorable outcomes can be achieved with RIC approaches in pediatric patients in remission who are ineligible for myeloablative transplantation. This study was registered at www.clinicaltrials.gov as #NCT00795132.