Life expectancy of patients with severe transfusion-dependent beta-thalassemia (TDT) remains below that of the general population. Allogenic hematopoietic stem cell transplantation (HSCT) is the standard curative treatment. Due to the paucity of matched donor (MD) availability, haploidentical HSCT (haplo-HSCT) is a reasonable alternative. Twenty patients with TDT (median age 10 years; range 2–23) received either a matched sibling donor (MSD; n = 7) or a haplo-HSCT (n = 13) in a single center (Regensburg, Germany) between 2016 and 2022, including two patients referred for a haplo-HSCT as rescue failing prior MD- and haplo-HSCT, respectively. The conditioning regimen consisted of anti-thymocyte globulin (ATG; Grafalon®), treosulfan, thiotepa, and fludarabine (FTT). Immunosuppression consisted of a calcineurin inhibitor and mycophenolate mofetil (MMF). At a median follow-up of 37 months (range 6–90), overall survival (OS) was 100% with a disease-free survival (DFS) of 100% in MSD and 92% in haplo-HSCT, respectively. Two patients in haplo-HSCT experienced graft failure, one achieving DFS after a second haplo-HSCT. No acute graft-versus-host disease (aGvHD) ≥ °III or severe chronic GvHD (cGvHD) were observed. No sinusoidal obstruction syndrome (SOS) was observed in this high-risk population. Treosulfan-based T-cell depleted haplo-HSCT can achieve comparable OS and DFS even in young adult TDT patients with no SOS/VOD.