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Background: Measurable residual disease (MRD) status before allogeneic hematopoietic stem cell transplantation (AHSCT) is commonly associated with a high risk of relapse. It is still uncertain whether AHSCT could overcome the negative impact of MRD positivity (MRD+), especially in patients with high-risk Philadelphia negative acute lymphoblastic leukemia (Ph-negative ALL). Materials and methods: An observational retrospective study was conducted on patients with high-risk Ph-negative ALL who underwent AHSCT between January 2005 and June 2022. The patients selected were in complete remission (CR): with 80% in CR1 (n = 69) and 20% in CR2 (n = 17). Graft sources were bone marrow (BM) in 71% of patients and peripheral blood stem cells in 29% of patients. The conditioning regimen was TBI or chemotherapy-based (CT). Bone marrow MRD level was quantified using 4-6 color multiparametric flow cytometry (MFC). The threshold for MRD positivity was ≥ 0.1%. Results: The study included 86 patients (45 B-ALL and 41 T-ALL) with a median age of 18 years (range, 4–55 years). The median level of MRD pre-AHSCT (pre-MRD) was 0.4×10-3 (range, 0.01-75.6×10-3). After a median follow-up of 25 months (range 1-205 months), the cumulative incidence of relapse (CIR) was significantly higher in the MRD+ group (39% vs. 20%, p = 0.04). The median time of relapse post-AHSCT was 14 months (range, 1-203 months) in the MRD+ group and 32 months (range, 4-209 months) in the MRD- group (p = 0.28). Non-relapse mortality (NRM) was 15% in both groups (p = 0.97). The 2-year estimated overall survival (OS) and event-free survival (EFS) were 61% vs. 74% (p = 0.07) and 58% vs. 70% (p = 0.10) in the MRD+ and MRD- groups, respectively. A subgroup analysis in MRD+ patients showed that a TBI-based conditioning regimen was distinctly associated with lower CIR (22% vs. 60% respectively, p = 0.04), improved OS (82% vs. 36% respectively, p = 0.007) and better EFS (73% vs. 38%, p = 0.04) compared to CT-based. In a multivariate analysis, pre-AHSCT MRD+ status and non-TBI-based conditioning were significantly associated with inferior OS (OR, 2.30; 95% CI, [1.027-5.168], p = 0.04 and OR, 3.91; 95% CI, [1.624-9.418], p = 0.002, respectively). The only predicting factor of lower EFS was the non-TBI-based regimen (OR, 2.82; 95% CI, [1.308-6.097], p = 0.008). Non-TBI-based and CR2 were significantly associated with higher CIR (OR, 6.25; 95% CI, [1.947-20.055], p = 0.002 and OR, 4.74; 95% CI, [1.197-18.791], p = 0.03, respectively). Peripheral stem cell source was significantly associated with higher NRM (OR, 6.55; 95% CI, [1.488-28.820], p = 0.01). Conclusion: High-risk Ph-negative ALL patients with MRD ≥ 10-3 prior AHSCT had lower OS compared to MRD- patients and may benefit from TBI as a conditioning regimen before AHSCT.