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Despite the promising therapeutic potential of regulatory T cells (Treg) in animal studies of graft-versus-host disease (GVHD), little is known about their effect on human GVHD. Whether Treg are capable of ameliorating GVHD tissue damage has never been demonstrated in humans. It is also unknown whether Treg modulation of GVH histopathologic damage relies on their presence during effector T-cell priming, or whether allogeneic Treg are safe to use clinically.To address these questions, we used an in vitro human skin explant GVHD model, which mimics the physiopathology of GVHD. First, “donor”-derived CD8+ T cells were stimulated with human leukocyte antigen-unmatched “recipient” dendritic cells (priming phase), then primed “donor” CD8+ T cells were co-cultured with “recipient” skin to induce GVH tissue damage (effector phase). “Donor”-derived Treg were added at the priming or effector phase of the GVH response. Histopathologic changes in the skin were evaluated using a clinically validated GVHD scoring system.“Donor”-derived Treg significantly reduced the severity of GVH histopathologic damage when present during T-cell priming. In contrast, Treg failed to prevent GVH tissue damage when added to the skin co-culture (effector phase), concurrently with primed T cells. Importantly, “donor” Treg alone did not induce GVH tissue damage. Delayed Treg addition led to reduced and impaired Treg suppression of CD8+ T-cell activation and their cytolytic function.“Donor”-derived Treg effectively suppress CD8+ T-cell-mediated GVH tissue damage but are critically required during priming of effector T cells. “Donor”-derived Treg seem to be safe and do not induce GVH histopathologic damage.