Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT. In 69 patients with a BCR-ABL mutation, KMT2A-AFF1 translocation, or blast cell hypodiploidy (< 45 chromosomes), 2-year EFS (but not OS) was significantly higher with TBI versus chemoconditioning (0.89 [95% CI, 0.71 to 0.97] v 0.60 [95% CI, 0.36 to 0.78], respectively; P = .0182).