A potent stimulation of fibroblast collagen production is one of the crucial pleotropic effects of transforming growth factor ? (TGF-?) and has been considered to play a crucial role in the pathogenesis of fibrotic diseases including Systemic Sclerosis and Pulmonary Fibrosis. This complex process involves numerous intracellular reactions mediated by canonical Smad-dependent or non-canonical pathways that transduce the extracellular stimuli into the nucleus. Here, we demonstrated that Simvastatin, a widely used statin, induces a potent inhibition of TGF-?1 profibrotic effects in cultured normal human dermal fibroblasts, and studied the molecular mechanisms involved in these effects. We also examined Simvastatin modulation of TGF-?1 induced fibroblast to myofibroblast transition. Normal human dermal fibroblasts were cultured with various concentrations of Simvastatin in the presence or absence of TGF-?1 (10ng/ml) for 24, 48, and 72 h. The effects of Simvastatin on TGF-?1 stimulation of COL1A1 expression and type 1 collagen production were examined. Assessment of Smad2/3 and Erk1/2 phosphorylation, chromatin immunoprecipitation assays for Sp1 transcription factor binding to the COL1A1 proximal promoter, siRNA-mediated RhoA knockdown, and F-actin immunofluorescence microscopy was performed to examine the molecular mechanisms involved.The results showed that Simvastatin caused a potent and dose-dependent abrogation of TGF-?1 stimulation of COL1A1 expression and type I collagen production in cultured normal human dermal fibroblasts. The molecular mechanisms of these effects were complex and involved reduction of Sp1 binding to the COL1A1 proximal promoter, decreased Erk1/2 phosphorylation and inhibition of Rho-A- mediated prenylation effects. Additional studies indicated that Simvastatin also prevented the TGF-?- induced phenotypic conversion of fibroblasts into activated myofibroblasts. Collectively, these results suggest that statins may be effective therapeutic agents for TGF-?1-mediated fibrotic diseases including Systemic Sclerosis and Pulmonary Fibrosis.