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Thy-1 (CD90) is a well-known marker of fibroblasts implicated in organ fibrosis, but its contribution to skin fibrosis remains unknown. We examined Thy-1 expression in scleroderma skin and its potential role as a biomarker and pathogenic factor in animal models of skin fibrosis. Skin from patients with systemic sclerosis demonstrated markedly elevated Thy-1 expression compared with controls, colocalized with fibroblast activator protein in the deep dermis, and correlated with the severity of skin involvement (modified Rodnan skin score). Serial imaging of skin from Thy-1 yellow fluorescent protein reporter mice by IVIS showed an increase in Thy-1 expression that correlated with onset and progression of fibrosis. In contrast to lung fibrosis, Thy-1–KO mice had attenuated skin fibrosis in both bleomycin and tight skin-1 murine models. Moreover, Thy-1 regulated key pathogenic pathways involved in fibrosis, including inflammation, myofibroblast differentiation, apoptosis, and multiple additional canonical fibrotic pathways. Therefore, although Thy-1 deficiency leads to exacerbated lung fibrosis, in skin it is protective. Moreover, Thy-1 may serve as a longitudinal marker to assess skin fibrosis.