Liver wound healing is an integrated process, in which hepatic stellate cells play a major role. We hypothesized that the cell-extracellular signaling protein, integrin-linked-kinase (ILK), is important in transducing signals from the extracellular matrix to stellate cells and thus plays a critical role in stellate cell activation and fibrogenesis during liver injury. Liver injury and subsequent stellate cell activation led to a 3-fold increase in ILK expression, and increased kinase activity. Overexpression of ILK in isolated stellate cells led to enhanced motility and adhesion, as well as increases in smooth muscle a actin and type I collagen mRNA expression. The effects of ILK on stellate cell phenotypes were PI3-kinase dependent. Forced expression of ILK in vivo led to increases in type I collagen, smooth muscle a actin, TGF-ß and EDA (extra domain A) fibronectin mRNAs (by 3.2, 3.5, 2.5 and 2.2-fold, respectively, n = 8, p < 0.05 for each vs. control), while inhibition of ILK in vivo led to significant reductions in these mRNAs. Morphometric analysis revealed that ILK overexpression led to a 31.4% increase in liver collagen content (n = 8, p< 0.05 vs. control); in contrast ILK knockdown in vivo led to a significant reduction in fibrogenesis. We conclude that ILK plays an important pathophysiological role in vivo in liver wound healing.