Background: Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. Procedure: We present our ten-year experience (October 2012-October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU) and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4yr) with acute myeloid leukemia (AML, n=17), myelodysplastic syndrome (MDS, n=4), or chronic myeloid leukemia (CML, n=2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was MSD PBSC (n=7), MUD PBSC (n=2), UCB (n=3) or haploidentical-BMT (n=11). Risk stratification was low (n=2), intermediate (n=15), high (=3) and very high risk (n=1). The two patients with CML had failed tyrosine kinase inhibitor therapies. Results: With a median follow-up of 39.6 months the relapse rate is only 4.5% with an OS 100%, PFS 95.5% and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the GvHD prophylaxis regimen significantly impacted grades II-IV aGvHD 66.7% versus 19.2% ( P=0.039) and cGvHD 66.7% versus 0% ( P=0.002) in the patients receiving matched sibling (MSD) or matched unrelated donor (MUD) PBSC compared to haplo-BMT respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor PBSCT ( P=0.025). Conclusions: Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT but in the setting of PBSC grafts with CSA-MTX GvHD prophylaxis it results in an unacceptably high incidence of GvHD.