Scleroderma is a disorder characterized by fibrosis of the skin and internal organs and autoimmunity. Whereas the cause is unknown, interleukin-4 and transforming growth factor-β have been postulated to play a major part in the fibrosis. To investigate the part played by these cytokines, we prepared TSK/+ mice with a targeted mutation in the interleukin-4Rα or transforming growth factor-β genes. The breeding failed to produce TSK/+ transforming growth factor-β –/– mice so analysis of the role of transforming growth factor-β was limited to TSK/+ transforming growth factor-β +/– mice. We observed that TSK/+ interleukin-4Rα –/– did not develop dermal thickening, and deletion of one allele of the transforming growth factor-β gene resulted in diminished dermal thickness compared with TSK/+ mice; however, the deletion of interleukin-4Rα or transforming growth factor-β had no effect on lung emphysema, which is another characteristic of TSK syndrome. Electron microscopic analysis of skin showed that the collagen fibrils in TSK/+ interleukin-4Rα –/– mice exhibit normal periodicity but have a smaller diameter than the fibers found in C57BL/6 mice. Analysis of skin and serum samples showed that the deletion of interleukin-4Rα or one allele of transforming growth factor-β prevented the increase of skin thickness paralleled with a decrease in the dermal hydroxyproline content and development of autoantibodies associated with TSK syndrome. These results demonstrate the importance of interleukin-4 and transforming growth factor-β for the development of cutaneous fibrosis in vivo and suggest an important part for these cytokines in wound healing and connective tissue maintenance in general.