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Graft-versus-host disease (GvHD) remains a major cause of morbidity and non-relapse mortality after allogeneic hematopoietic cell transplantation. Building on prior evidence implicating mitochondrial DNA (mtDNA) variation in myelodysplastic neoplasms (MDS), we investigated the prognostic impact of recipient and donor mtDNA variation on acute and chronic GvHD. Whole‑genome sequencing was performed on pretransplant samples from 494 MDS donor-recipient pairs (discovery cohort) from the Center for International Blood and Marrow Transplant Research (CIBMTR). Associations between mtDNA variations and acute GvHD grades II-IV (aGvHD24), grades III-IV (aGvHD34), and chronic GvHD (cGvHD) were assessed using cause-specific Cox proportional hazards models. Model discrimination was quantified using area under the curve (AUC). Findings were evaluated in an independent cohort of 295 MDS using targeted mtDNA deep sequencing. Among the recipient mtDNA gene associations identified in the discovery cohort, MT-ND2 for aGvHD34 (p = 1.1 × 10^-3) and MT-CYB for cGvHD (p = 3.6 × 10^-3) were independently validated, while MT-CO2, which was nominally associated with aGvHD34 in the discovery cohort, was also significant in the recipient validation cohort (p = 3.2 × 10^-3). Incorporating recipient mtDNA genes into the CIBMTR aGvHD Risk Index improved discrimination for aGvHD34 by 11% (p = 0.009). In conclusion, mtDNA variants may provide independent prognostic information for GvHD and may enhance current risk stratification when integrated with standard clinical parameters.