The skin is a major target organ for graft-versus-host disease (GVHD), the principal complication of allogeneic bone marrow transplantation. The purpose of the present study was to test whether mast cell degranulation might be related to early target cell injury in the development of acute GVHD. We employed two irradiated murine strain combinations, one in which disease was mediated by CD4⁺ effector T cells (B10.D2 → DBA/2), and the other by CD8⁺ effector T cells (B10.BR → CBA). As compared to controls, both models exhibited mast cell degranulation of differing extents and patterns, as well as dyskeratosis in the epidermis before the influx of effector lymphocytes. These results suggested that factors produced and released by degranulated dermal mast cells might contribute to early target cell injury. Accordingly, the possible role of tumor necrosis factor (TNF)-α, a cytokine recently discovered in mast cell granules, was investigated by the injection of anti – TNF-α antibody during the course of disease mediated by either CD4⁺ or CD8⁺ T cells. Although overall survival of recipients undergoing CD4⁺ T-cell – mediated GVHD was only slightly improved and the extent of mast cell degranulation was not affected by anti – TNF-α antibody treatment, the skin exhibited a significant diminution in the number of dyskeratotic cells/linear mm at 3–4 weeks post-transplantation. In contrast, anti – TNF-α antibody failed to enhance survival or reduce the number of dyskeratotic cells in the skin during CD8⁺ T-cell – mediated disease. Finally, to determine whether CD8⁺ T-cell–mediated GVHD was at all dependent upon mast cell involvement, the C3H.SW → B6WW^v strain combination was utilized, in which recipients were genetically deficient in mast cells. Onset of GVHD was significantly delayed in B6WW^v mice and was clearly correlated to the appearance and increase of de novo mast cells at later time points.