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Acute graft-versus-host disease (aGvHD) remains a substantial cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Limited studies explore the association between specific major histocompatibility complex (MHC) alleles and aGvHD or transplant-related mortality (TRM). After a noted clinical trend of higher TRM among a series of patients with aGvHD and MHC class I HLA- A   ∗ 01:01, we retrospectively evaluated transplant outcomes of 404 adult allo-HCT patients who underwent unmodified allografts between 03/2010 and 02/2017. HLA- A   ∗ 01:01 was expressed by 104 (25.7%) patients. In a univariate analysis, patients who underwent unmodified transplants and expressed HLA- A   ∗ 01:01 had a higher risk of TRM (HR 1.63 [95% CI: 1.05-2.53], p = 0.035). In a multivariate cause-specific Cox model, HLA- A   ∗ 01:01 was significantly associated with TRM after adjusting for grade II-IV aGvHD, conditioning regimen intensity, and age at transplant (HR 1.59 (95% CI: 1.02-2.48) p = 0.039). There were no significant differences in overall survival (OS), aGvHD, or chronic GvHD based on HLA- A   ∗ 01:01 expression. With confirmation in a larger cohort, these findings have potential implications for the selection of allograft type, conditioning regimen, and post-transplant monitoring for this high-risk population.