Background: The role of splenectomy prior to hematopoietic stem cell transplantation (HSCT) is controversial. Only few studies compared the outcomes of splenectomized and nonsplenectomized children with transfusion‐dependent thalassemia (TDT) undergoing allogeneic HSCTs.Methods: A retrospective analysis was undertaken on a transplantation cohort of TDT patients; August 1987‐December 2014 to compare transplant outcomes between splenectomized and nonsplenectomized groups.Results: Ninety‐six transplants in 86 TDT patients were analyzed. Sixteen patients were splenectomized before HSCTs. The splenectomized patients were significantly older (8.0 ± 1.9 vs 4.7 ± 0.6 years; P = 0.001), had larger livers and spleens (P = 0.001), and had a significantly shorter neutrophil engraftment time (absolute neutrophil count > 500/mm³; 15.0 ± 2.3 vs 19.2 ± 1.3 days; P = 0.004). Graft rejection occurred in 13.8% of the nonsplenectomized group, but not among the splenectomized patients. Though the splenectomized group's mortality rate was higher (25.0% vs 8.8%), this was not statistically significant (P = 0.491). The main causes of death in both groups were severe infections. The five‐year overall survival (OS) rate was better for the nonsplenectomized group (91.78% vs 75.00%; P = 0.06).Conclusions: Although splenectomies prior to HSCT for the TDT patients in our cohort were associated with faster neutrophil engraftments and lower rejection rates, they did not produce significantly better OS or affect the mortality. As the splenectomies did not provide any distinct advantages, this procedure should not be routinely performed as a pre‐HSCT regimen for TDT patients with splenomegaly. Better pre‐HSCT preparation for TDT patients, including early and adequate blood transfusions to avoid splenomegaly, is recommended.

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