A case of graft-vs.-host disease (GVHD) arising solely within an area affected by piebaldism is described. The patient, a 35-year-old woman with a single hypopigmented patch on the right leg present since birth, had received an allogeneic bone marrow transplant (BMT) from an HLA-identical sibling donor, for treatment of a myelodysplastic syndrome (MDS). Beginning on day +38 post-BMT, the patch developed changes which were histologically consistent with GVHD. Syngeneic mixed epidermal cell-lymphocyte reaction (MECLR) testing of tissue from the patch, and from adjacent normal skin, showed differences which suggest that piebaldism-affected skin is immunologically different from normal skin. These findings may offer new insight into the pathophysiology of this disorder.