Pulmonary fibrosis is an interstitial disorder of the lung parenchyma whose mechanism is poorly understood. Potential mechanisms include the infiltration of inflammatory cells to the lungs and the generation of pro-inflammatory mediators. In particular, idiopathic pulmonary fibrosis is a progressive and fatal form of the disorder characterized by alveolar inflammation, fibroblast proliferation and collagen deposition. Here, we investigated the role of cytosolic phospholipase A₂ (cPLA₂) in pulmonary fibrosis using cPLA₂-null mutant mice, as cPLA₂ is a key enzyme in the generation of pro-inflammatory eicosanoids. Disruption of the gene encoding cPLA₂ (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration. Bleomycin-induced overproduction of thromboxanes and leukotrienes in lung was significantly reduced in cPLA₂-null mice. Our data suggest that cPLA₂ has an important role in the pathogenesis of pulmonary fibrosis. The inhibition of cPLA₂-initiated pathways might provide a novel therapeutic approach to pulmonary fibrosis, for which no pharmaceutical agents are currently available.