Background: CD44v6 and c-Met contribute to TGF-␤1 signaling in interstitial lung disease (ILD). Results: CD44v6/TGF-␤1 signaling regulates activation of ILD fibroblasts, whereas the HGF/Met pathway down-regulates the activation. Conclusion: Overexpression of HGF in ILD fibroblasts sustains the TGF-␤1-regulated CD44v6 expression that promotes collagen synthesis. Physiological concentrations of HGF are insufficient to influence its antifibrotic effect in these cells. Significance: These results should provide CD44v6 as new drug target to treat ILD.