PURPOSE: Disease relapse and graft-versus-host disease (GVHD) represent significant clinical challenges for high-risk hematological malignancies (HM) patients undergoing HLA-matched sibling donor transplantation (MSDT). How to balance the effect of GVHD and Graft versus leukemia (GVL) remains unclear for high-risk HM patients receiving MSDT. Here, we conducted a retrospective study to compare the efficacy in preventing disease relapse of 2 lymphocyte-depleting antibodies (r-ATG vs p-ALG) as the GVHD prevention strategy. METHOD: A retrospective analysis was conducted on 48 patients with high-risk HM patients who underwent MSDT at our center from January 2019 to January 2024. Among them, 22 patients were in the p-ALG group (45mg/kg), and 26 patients were in the r-ATG group (3.5-4.5mg/kg). The primary end point of this study was disease relapse. RESULTS: We found that the p-ALG group had a higher 3-year cumulative incidence of chronic GVHD than the r-ATG group (64.4% ± 13.6% vs. 28.8% ± 9.7%, P = 0.016). There was no significant difference in total acute GVHD (aGVHD) (54.5% ± 11% vs.26.9% ± 8.9%, P = 0.81) and 3-year extensive cGVHD (20.3% ± 11.3% vs. 7.9% ± 5.5%, P = 0.27) between the 2 groups. In terms of patient prognosis, the p-ALG group showed a higher 3-year overall survival rate compared to the r-ATG group (100% vs. 75.5% ± 8.8%, P = 0.039). The 3-year disease-free survival (DFS) rate was significantly higher in the p-ALG group compared to the r-ATG group (95.5% ± 4.4% versus 61% ± 10.6%, P = 0.046). Furthermore, the p-ALG group exhibited a longer duration of disease remission after transplantation, as evidenced by a lower 3-year cumulative incidence of post-transplantation Minimal Residual Disease positivity (post-MRD+) compared to the r-ATG group (4.5% ± 4.4% versus 40.5% ± 11%, P = 0.022). CONCLUSION: In comparison to r-ATG, the administration of low-dose p-ALG (45mg/kg) in high-risk HM patients receiving MSDT is associated with an increased incidence of GVHD but results in a more favorable survival prognosis.