The inhalation of vanadium pentoxide (V 2 O 5) results in bronchitis and airway fibrosis. The lung fibrotic response to V 2 O 5 partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis. We previously reported that STAT-1 is a protective factor and mice lacking STAT-1 are more susceptible to lung fibrosis. We also reported that V 2 O 5-induced STAT-1 phosphorylation in lung fibroblasts requires H 2 O 2 and de novo protein synthesis. In this study, we identified IFN-β as the protein that mediates STAT-1 activation by V 2 O 5 in normal human lung fibroblasts and identified NADPH and xanthine oxidase systems as sources of H 2 O 2 that drive IFN-β gene expression. STAT-1 phosphorylation was decreased with neutralizing Abs to IFN-β as well as an inhibitor of JAK. V 2 O 5 also increased transcription of an IFN-inducible and STAT-1-dependent chemokine, CXCL10. Inhibition of H 2 O 2-generating enzyme systems NADPH oxidase by apocynin and xanthine oxidase by allopurinol individually reduced STAT-1 phosphorylation. Apocynin and allopurinol also decreased V 2 O 5-induced IFN-β mRNA levels and CXCL10 expression. IFN-α transcription was inhibited only by allopurinol. Taken together, these data indicate that fibroblasts play a role in the innate immune response to vanadium-induced oxidative stress by synthesizing IFN-β and activating STAT-1 to cause growth arrest and increase levels of CXCL10, a potent antifibrotic factor. This mechanism is postulated to counterbalance profibrogenic mechanisms that follow V 2 O 5 injury.