To determine graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation (HSCT), we studied the outcome of consecutive children with acute lymphoblastic leukemia (ALL) who received fully matched marrow allografts comparing relapse rate post HSCT between matched sibling donor (MSD) and matched unrelated donor (MUD) recipients. Furthermore, we estimated event-free survival (EFS) on the basis of the occurrence of acute graft-versus-host disease (aGVHD). Between 1998 and 2006 we performed 37 fully MSD and 36 fully MUD HSCTs. All patients received identical conditioning regimens with cyclophosphamide/total body irradiation and dual GVHD prophylaxis with cyclosporine (CSA) and methotrexate (MTX). Three-year cumulative incidence of relapse for the MSD and MUD groups were 55.6+/-12.3 and 22.0+/-8.1%, respectively (P=0.03). Three-year EFS according to aGVHD was 32.7+/-12.2% for no aGVHD, 61.2+/-10.0% for grade I-II aGVHD and 66.7+/-11.1% for grade III-IV aGVHD. Three-year EFS and overall survival (OS) were 40.5+/-11.6, 49.1+/-9.5% for the MSD group, and 60.5+/-8.7, 62.3+/-8.4% for the MUD group. In children with ALL receiving dual GVHD prophylaxis, relapse rate is significantly higher among recipients of MSD compared to MUD transplantation, which may in part be attributed to a better GVL effect with the unrelated graft.