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Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the only curative treatment for children with transfusion-dependent (TD) β-thalassemia major. When available, HLA-matched related donor allo-HSCT should be performed as early as possible. This retrospective study analyzes the outcomes of 68 consecutive pediatric patients (pts) with β-thalassemia who underwent Allo-HSCT with HLA-identical donors at our center. Materials and Methods: From June 1999 to July 2018, 68 consecutive pts with TD major β-thalassemia underwent allo-HSCT from matched related donors in our institution (HLA identical sibling: 56, phenotypically: 9, cord blood: 3). The median age: 8 years (4-18) with 45 pts (66%) older than 7 years. Sex-ratio: 1,42. The median number of red blood cell transfusions was 81 units/pt (54-312). Iron chelation therapy was irregular in 46 pts (67,6%) and median serum ferritin at transplant was 1334 ng/ml (103-10220). Liver biopsy was performed in all pts and Pesaro risk classification was determined: Class 1 : 10 (14,7%), Class 2 : 26 (38,3%) and Class 3 : 32 (47%). Splenectomy had been performed in 30 pts (44%). The median interval between diagnosis and transplant was 84 months (36-192). The preparative conditioning regimens consist on oral Busulfan 500 mg/m2 or adjusted-Busilvex, Ciclophosphamide 200 mg/kg and Thymoglobulin 10 mg/kg (Pesaro class 1-2); Busulfan 14 mg/kg or adjusted-Busilvex, Ciclophosphamide 120 mg/kg and Thymoglobulin 10 mg/kg (Pesaro class 3); adjusted-Busilvex, Thiotepa 10mg/kg and Fludarabine 160 mg/m2 (Cord blood). GVHD prophylaxis consisted of Ciclosporin combined with short Methotrexate, or Ciclosporin alone (for cord blood). Stem cell sources : peripheral blood stem cells in 57 pts (83,8%) with a mean CD34+ cell count of 10,81x106 /kg (3,94-37,9), bone marrow in 8 pts with a mean Nucleated Cell (NC) count of 4,26 x 108 /kg and cord blood in 3 pts with a mean NC count of 4,8 107 /kg. Follow-up (as of May 2025), minimum 82 months, maximum 296 months. Results: Neutrophil engraftment occured at a median of 17 days (9-69). Transfusions were required in all pts with an average of red blood cells: 5 units/pt (1,5-16) and Platelets concentrates: 4 units/pt (0-32). Graft failure occured in 9 pts (4 with Pesaro class 3), they received a stem cell boost with no benefit observed except in one pt. Veino-occlusive disease was observed in 7 pts (10,2%). Acute GVHD grade II-IV occured in in 13 (23,2%) of pts and extensive chronic GVHD in 6 pts (11,5%). Fifty-one pts (75%) are alive with a median follow up of 120 months (82-296) with in 42 pts (82,3%) with total donor chimerism. Seventeen pts (25%) died mainly do to graft failure:3, infection:2, VOD:1, GVHD: 7, TMA:1, oral cancer :1, hydrocephalus: 1, hepatic cirrhosis :1. Overall survival (OS) at 25 years was 69%. OS by Pesaro class was 68% for class 1-2 and 75% for class 3. Conclusion: Despite a high proportion of pts advanced risk factors (older age, high Pesaro class), allo-HSCT provided sustained long-term survival in this cohort. Early transplantation remains critical to improving outcomes in TD β-thalassemia major.