Tripe palms are thickened, moss-like or velvety textured exaggerations of the normal dermatoglyphics. The disease belongs to the spectrum of papulosquamous paraneoplastic syndromes. Although suspected, the role of transforming growth factor-α (TGF-α) has not been clearly established. A 54-year-old man with systemic mastocytosis presented with thickening and darkening of the palms and soles. We performed skin biopsies for light microscopy (including toluidine blue), in situ hybridization and double labelling, and determination of serum tryptase, histamine and TGF-α levels. Toluidine blue stained the mast cells that had massively infiltrated the dermis. Tripe palm samples showed extensive hyperkeratosis. The TGF-α probe reacted strongly with the mast cells that also reacted with the antitryptase monoclonal antibody. Elevated tryptase, histamine and TGF-α levels prior to interferon-alfa administration decreased under treatment. The demonstration of TGF-α in infiltrating mast cells, the clinical regression of tripe palms and the lowering of the serum level and the mast cell molecular signal of the cytokine when systemic mastocytosis was controlled by interferon-alfa, suggest a key role for TGF-α in this cutaneous paraneoplastic syndrome.