Rationale: In experimental models, lung fibrosis is dependent upon TGF signaling. TGF is secreted in a latent complex with its propeptide and TGF activators release TGF from this complex. Because the integrin v6 is a major TGF activator in the lung, inhibition of v6-mediated TGF activation is a logical strategy to treat lung fibrosis. Objective: To determine, by genetic and pharmacologic approaches, whether murine radiation-induced lung fibrosis is dependent upon v6. Methods: Wild type mice, v6-deficient (Itgb6^-/-) mice, and mice heterozygous for a Tgfb1 mutation that eliminates integrin-mediated activation (Tgfb1^+/RGE) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-v6 mAb or a soluble TGF receptor fusion protein. v6 expression was determined by immunohistochemistry. Fibrosis, inflammation and gene expression patterns were assessed 20-32 weeks post-irradiation. Measurements and main results: 6 integrin expression increased within the alveolar epithelium 18 weeks post-irradiation, just prior to onset of fibrosis. Itgb6^-/- mice were completely protected from fibrosis but not from late radiation-induced mortality. Anti-v6 therapy (1-10 mg/kg/wk) prevented fibrosis, but only higher doses (6-10 mg/kg/wk) caused lung inflammation similar to that in Itgb6^-/- mice. Tgfb1-haploinsufficient mice were also protected from fibrosis. Conclusions: v6-mediated TGF activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for v6 in distinct fibrosis models. Inhibition of v6-mediated TGF activation is a promising new approach for anti-fibrosis therapy.