Pulmonary fibrosis is characterized by alterations in fibroblast phenotypes resulting in excessive extracellular matrix accumulation and anatomic remodeling. Current therapies for this condition are largely ineffective. Peroxisome proliferator-activated receptor- (PPAR-) is a member of the nuclear hormone receptor superfamily whose activation produces a number of biological effects including alterations in metabolic and inflammatory responses. The role of PPAR- as a potential therapeutic target for fibrotic lung diseases remains undefined. In this study, we show that both normal human lung fibroblasts and those obtained from patients with idiopathic interstitial pneumonias (IIPs) express PPAR-. Treatment of lung fibroblasts and myofibroblasts with PPAR- agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR- agonists, including a constitutively active PPAR- construct (VP16-PPAR-), inhibit the ability of transforming growth factor (TGF)-1 to induce myofibroblast differentiation and collagen secretion. PPAR- agonists also inhibit fibrosis in a murine model even when administration is delayed until after the initial inflammation has largely resolved. These observations indicate that PPAR- is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR- ligands as novel therapeutic agents for fibrotic lung diseases.