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ABSTRACT Although post‐transplant cyclophosphamide (PTCY)‐based prophylaxis has become a widely adopted strategy for preventing graft‐versus‐host disease (GVHD) in 9 out of 10 HLA‐mismatched unrelated donors (MMUDs), allogeneic hematopoietic cell transplants (allo‐HCTs), data on the safety and efficacy of PTCY in this setting remain limited. This single‐center study investigates the outcomes of 94 adults with hematological malignancies undergoing MMUD allo‐HCT with PTCY and tacrolimus (Tac) (PTCY‐Tac) between 2014 and 2023. The median age was 53 years, and 60.6% were male. Peripheral blood stem cells were infused in all cases. By Day +100, the cumulative incidence of Grades II–IV and Grades III and IV acute GVHD were 33.0% and 9.7%, with 2‐year incidence of moderate‐to‐severe chronic GVHD at 12.6%. By Day +30, 40.8% of patients experienced bacterial bloodstream infections, and 52.4% had cytomegalovirus (CMV) reactivation before letermovir prophylaxis. With letermovir's introduction, CMV reactivation rates dropped significantly, with only one case reported. At 3 years, overall survival was 60.8%, non‐relapse mortality was 23%, and the cumulative incidence of relapse was 24.5%. HLA Class I or II mismatches did not affect key outcomes or GVHD rates. These findings demonstrate that PTCY‐Tac offers effective GVHD prevention and favorable outcomes in MMUD allo‐HCT, supporting its application for patients without fully matched donors. [ABSTRACT FROM AUTHOR]