Murine sclerodermatous graft-versus-host disease (Scl GVHD), produced by transplanting B10.D2 bone marrow and spleen cells to lethally irradiated BALB/cJ mice, is a model for human scleroderma. Mice with Scl GVHD have skin thickening, lung fibrosis, cutaneous mononuclear cell infiltration, and upregulation of cutaneous transforming growth factor β1 (TGF-β1) and type I collagen mRNAs by day 21 after bone marrow transplantation. Elevated TGF-β1 appears to be the critical cytokine driving fibrosis in Scl GVHD, which can be prevented with antibodies to TGF-β administered early in disease. Here we demonstrate that we can also prevent skin thickening in mice with Scl GVHD with a naturally occurring antagonist to TGF-β1, human latency-associated peptide (LAP). By quantitative real-time PCR analysis and immunostaining, LAP treatment also abrogates the upregulation of cutaneous TGF-β1 and connective tissue growth factor mRNAs and type I collagen synthesis in Scl GVHD. In contrast to anti-TGF-β antibodies, LAP at 4 ng total per mouse has no significant suppressive effect on cutaneous influx of T cells and monocytes or immune cell activation. LAP may be a potential new therapy in scleroderma and other TGF-β-driven fibrosing disease that targets TGF-β more specifically, without affecting systemic critical roles of TGF-β on immune cell function.