Lung inflammatory cells of patients with idiopathic pulmonary fibrosis (IPF) were evaluated for their ability to injure 51Cr-labeled AKD alveolar epithelial cells in the presence and absence of IPF alveolar epithelial lining fluid (ELF). The IPF cells were spontaneously releasing exaggerated amounts of superoxide (O.2) and hydrogen peroxide (H2O2) compared with normal (P less than 0.02). Cytotoxicity of the AKD cells was markedly increased when the IPF inflammatory cells were incubated with autologous ELF (P less than 0.02). The majority of IPF patients had ELF myeloperoxidase levels above normal (P less than 0.002). Incubation of IPF ELF with AKD cells in the presence of H2O2 caused increased cellular injury (P less than 0.01 compared with control), which was suppressed by methionine, a myeloperoxidase system scavenger. IPF patients with high concentrations of ELF myeloperoxidase deteriorated more rapidly than those with low ELF myeloperoxidase (P less than 0.05). Thus, IPF is characterized by an increased spontaneous production of oxidants by lung inflammatory cells, the presence of high concentrations of myeloperoxidase in the ELF of the lower respiratory tract, and a synergistic cytotoxic effect of alveolar inflammatory cells and ELF on lung epithelial cells, suggesting oxidants may play a role in causing the epithelial cell injury of this disorder.