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Aim Mortality of Acute Graft vs. Host Diseases (aGvHD) after Liver Transplantation (LT) can be as high as 70–100%, due to delays in diagnosis and severity of complications. Based on a large LT cohort with long term follow up, we investigated the role of donor chimerism (D%) in supporting expeditious aGvHD diagnosis and monitoring disease control. Methods 145 of 1478 recipients with LT during 9/2007-12/2017 were clinically suspected to have aGvHD and tested for D% with peripheral blood (PB), CD3 + (T), CD8 + T, NK, and B lymphocytes by short tandem repeat (sensitivity 5%). D% at initial testing and peak stage, POD of aGvHD resolution, and aGvHD related mortality were retrospectively analyzed. Clinical suspicions with CD8 + T D% >25% were initially treated with methylprednisolone and/or reduced immunosuppression. Thymoglobulin was added to cases with no improvement after initial therapy. Results The D% in PB was uninformative. The highest D% was seen in CD8 + T cells followed by T cells and NK cells. Of 145 recipients with D% test, 27 had D% > 5, these patients were then graded into clinical severity as C0-3. Nine patients in C0 had no clinical evidence of aGvHD, whereas 18 patients were graded as C1-3. C2 and C3 (n = 9) had average CD8 + T D% ⩾ 75±23% at initial testing and ⩾ 86±24% at peak D% stages, which were significantly higher than that of C1 (n = 9) with p Conclusions The D% of CD8 + T cell is a sensitive and correlative indicator for timely diagnosis and effective monitoring of aGvHD after LT. High D% of CD8 + T from initial testing and peak phase was associated with aGvHD related mortality or prolonged resolution of this disease. Early detection of D% of CD8 + T before the donor immune system fully engrafted is critical for recovering from the damage of aGvHD following LT.