Abstract: The tight skin (Tsk) mouse develops many pathological changes seen in human scleroderma, such as increased collagen content and mast cell density. Although associations between mast cell expansion and skin fibrosis have been reported, the mechanisms underlying mast cell accumulation remain unclear. In this study, we have measured the density of skin mast cells in Tsk mice and their normal littermates (pa/pa) of 4–36 weeks of age, and in the skin heterografted between Tsk and pa/pa mice. Cytokines related to mast cell differentiation, proliferation and migration were examined by using RNase protection assays. Skin mast cell density in Tsk mice was significantly increased from 12 weeks of age, compared to that in pa/pa mice. The expression of transforming growth factor-β1 (TGF-β1), and to a lesser extent, stem cell factor (SCF) and interleukin-15 (IL-15) mRNA was higher in Tsk mice, compared to that in control mice. Mast cell density was unchanged in Tsk skin grafted onto pa/pa hosts, but dramatically increased in pa/pa skin grafted onto Tsk hosts. This latter mast cell hyperplasia was associated with the increases in mRNA levels of TGF-β1, SCF and IL-15, whereas little change in cytokine levels was seen in heterografted Tsk skin. These results suggest that locally produced cytokines in Tsk skin influence mast cell accumulation in this animal model of human scleroderma.