Post-transplant cyclophosphamide (PT-Cy)-based graft-versus-host disease (GVHD) prophylaxis is progressively being used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched related donors (MRD). However, information regarding the transfusion needs in this setting is lacking. to compare red blood cell (RBC) and platelet units transfused and time to transfusion independence according to the GVHD prophylaxis in MRD HSCT. We performed a matched-pair analysis comparing the transfusion requirements and the clinical outcomes of patients who received a MRD peripheral blood HSCT using PT-Cy from January 2017 until June 2021 (n = 100) with historical MRD transplants using standard cyclosporine A-based prophylaxis (n = 100). Neutrophil engraftment was significantly delayed in the PT-Cy group as compared with the CsA group (16 days vs. 13 days; P = 0.003). PT-Cy was associated with increased RBC (median, 5 units vs. 4; P = 0.04) and platelet transfusion requirements (median, 6 units vs. 3; P = 0.01) during the first 30 days after transplant. The proportion of patients requiring platelet transfusion during days 31 to 90 after transplant was also higher in the PT-Cy cohort (55% vs. 25%; P < 0.0001). In multivariate analysis, PT-Cy was associated with delayed RBC and platelet transfusion independence ([Hazard ratio [HR] = 0.61; P = 0.007 and HR = 0.51; P < 0.0001, respectively). Cumulative incidence at 100 days of BK polyomavirus (BKPyV)-associated haemorrhagic cystitis grade ≥ 2 was higher in the PT-Cy cohort (34% vs. 12%; P < 0.0001). However, PT-Cy resulted in lower rates of acute GVHD grade II-IV (100-days cumulative incidence 57% vs. 23%; P < 0.0001) and moderate to severe chronic GVHD (1-year cumulative incidence 49% vs. 28%; P = 0.003), as well as improved 2-year overall survival (74% vs. 56%; P = 0.01). Our study shows that PT-Cy increases transfusion burden in MRD HSCT. However, it results in a low incidence of severe GVHD, with encouraging survival outcomes.