Scleroderma fibroblasts exhibit numerous phenotypic differences when compared with healthy skin fibroblasts. Some of these differences, in particular overexpression of collagen type I and other extracellular matrix proteins, parallel the effect of transforming growth factor-β (TGF-β) on dermal fibroblasts, suggesting that the scleroderma fibroblast phenotype may result from activation of autocrine TGF-β signaling. To test this hypothesis we examined the role of TGF-β Type I and Type II receptors in regulating collagen type I transcription. We have shown that overexpression of either Type I or Type II receptors significantly (3–4-fold) increases α2 (I) collagen promoter activity in transient transfection assays in dermal fibroblasts. Addition of anti-TGF-β antibody abolished, whereas addition of plasmin enhanced, the stimulatory effect of receptor overexpression on collagen promoter activity, suggesting that this effect depends on autocrine TGF-β. Moreover, these cotransfection experiments indicated that expression levels of TGF-β receptors is a limiting factor in the autocrine regulation of collagen type I transcription by TGF-β. Comparison of the TGF-β receptor Type I and Type II mRA expression levels in scleroderma and normal fibroblasts have indicated elevated expression (2-fold) of both receptor types in scleroderma cells, which correlated with increased binding of TGF-β. Significantly, elevated TGF-β receptor levels correlated with elevated α2 (I) collagen mRNA levels. These results suggest that the elevated production of collagen type I by scleroderma fibroblasts results from overexpression of TGF-β receptors.