TCRαβ/CD19-cell depletion is a promising graft manipulation technique frequently used in the context of HLA-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of ex-vivo T cell-depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median value of 47.6 months for surviving patients). With a 5-year cumulative incidence of non-relapse mortality of 5.2% (95% confidence interval, CI, 2.8-8.8) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9-29.2), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI 68.6-80.9) and 71.6% (95% CI 64.4-77.6), respectively. Cumulative incidence of both grade II-IV acute and chronic GvHD were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including also type of disease, use of total body irradiation in the conditioning regimen [hazard ratio (HR) 0.5 (95% CI, 0.26-0.98, p=0.04)], disease status at HSCT [CR>3 versus CR1/2; HR 2.23 (95% CI, 1.20-4.16, p=0.01] and high levels of pre-HSCT minimal residual disease [HR 2.09 (95% CI, 1.01-4.33, p=0.04)] were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable to those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted.