We compared the outcomes of 298 patients with acute lymphoblastic leukemia in first or second complete remission (CR1 or CR2) receiving HLA-matched sibling allografts after cyclophosphamide and total body irradiation (Cy-TBI) conditioning with 204 patients receiving etoposide and TBI. Consequently, 4 groups were compared: Cy-TBI <13 Gy (n = 217), Cy-TBI > or =13 Gy (n = 81), etoposide-TBI <13 Gy (n = 53), and etoposide-TBI > or =13 Gy (n = 151). Analyses of relapse, leukemia-free survival (LFS), and survival were performed separately for CR1 and CR2 transplantations. Transplant-related mortality did not differ by conditioning regimen. In CR1, there were also no significant differences in relapse, LFS, or survival by conditioning regimen. In CR2, these outcomes differed among conditioning groups. In comparison with Cy-TBI <13 Gy, the risks of relapse, treatment failure (inverse of LFS), and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses > or =13 Gy. For both CR1 and CR2 transplantations, causes of death were similar among the groups; disease recurrence accounted for 47% of deaths. We conclude that for HLA-identical sibling allografts for acute lymphoblastic leukemia in CR2, there is an advantage in substituting etoposide for Cy or, when Cy is used, in increasing the TBI dose to > or =13 Gy.