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Allogeneic hematopoietic stem cell transplantation is curative for transfusion‐dependent thalassemia, but mixed chimerism (MC) may herald graft rejection. We report a child who failed bone marrow transplant (BMT) from matched unrelated donor (MUD) successfully salvaged with haploidentical peripheral blood stem cell transplant (PBSCT), but had MC in T‐lymphocyte compartment despite near‐complete donor chimerism in myeloid compartment. MC was successfully improved by repeated CD45RA‐depleted donor lymphocyte infusion (DLI). A 2‐year‐old Chinese girl with beta‐thalassemia major underwent 12/12‐MUD BMT with HU/AZA/Cy/Flu/Bu/TT conditioning resulted in graft rejection. As donor refused second donation, rescue haploidentical PBSCT was performed with alemtuzumab/fludarabine/treosulfan conditioning. Harvest product was CD3/CD45RA depleted with extra products cryopreserved. Split cell chimerism performed 1‐month after haplo‐transplant showed 97% mother, 3% MUD, and 0% host for granulocytes but 38% mother, 62% MUD, and 0% host for CD3 + T cells. In view of low haploidentical donor chimerism in T‐lymphocyte compartment, CD45RA‐depleted DLI using cryopreserved product was performed on day + 38, after thymoglobulin 3 mg/kg given as T‐cell depletion 3 days beforehand. T‐cell chimerism improved to 51% mother and 49% MUD post‐DLI. Second cryopreserved CD45RA‐depleted DLI was given 17 days after the first DLI (day + 55), and 100% full chimerism of mother's T cells was gradually established without significant graft‐versus‐host disease (GVHD) or viral reactivation. To conclude, split lineage chimerism determination is beneficial to guide management strategy. For MC in T‐cell compartment, CD45RA‐depleted DLI is a potential alternative to unselected T cells as it carries lower risk of GVHD and infection. [ABSTRACT FROM AUTHOR]