Fibrosis represents a common pathway leading to organ failure and death in many diseases and has no effective therapy. Dysregulated repair and excessive tissue scarring provides a unifying mechanism for pathological fibrosis. The protein phosphatase and tensin homolog (PTEN) acts to dephosphorylate proteins, which promotes tissue repair and thus could be a key fibrogenic mediator. To test this hypothesis, we first showed that PTEN expression was reduced in skin fibroblasts from patients with the fibrotic autoimmune disease diffuse systemic sclerosis (dSSc). To evaluate whether this deficiency could be sufficient for fibrogenesis in vivo, we deleted PTEN in adult mouse fibroblasts. Compared with littermate control mice, loss of PTEN resulted in a 3-fold increase in dermal thickness due to excess deposition of collagen. PTEN-deleted fibroblasts showed elevated Akt phosphorylation and increased expression of connective tissue growth factor (CTGF/CCN2). Selective inhibition of the phosphatidylinositol 3-kinase/Akt pathway reduced the overexpression of collagen and CCN2 by PTEN-deficient fibroblasts. Overexpression of PTEN reduced the overexpression of type I collagen and CCN2 by dSSc fibroblasts. Thus, PTEN appears to be a potential in vivo master regulator of fibrogenesis; PTEN agonists may represent anti-fibrotic treatments.