Hepatocyte transplantation is restricted by the impaired ability of hepatocytes to engraft and survive in the damaged liver. Understanding the mechanisms that control this process will permit the development of strategies to improve engraftment. We studied changes in liver matrix during acute injury and delineated the mechanisms that perturb the successful adhesion and engraftment of hepatocytes. Collagen IV expression was increased in sinusoidal endothelium and portal tracts of fulminant hepatic failure explants, whereas there were minimal changes in the expression of fibronectin, tenascin, and laminin. Using an in vitro model of cellular adhesion, hepatocytes were cultured on collagen-coated plates and exposed to serum from patients with liver injury to ascertain their subsequent adhesion and survival. There was a rapid, temporally progressive decrease in the adhesive properties of hepatocytes exposed to such serum that occurred within 4 hours of exposure. Loss of activity of the β1-integrin receptor, which controls adhesion to collagen, was seen to precede this loss of adhesive ability. Addition of the β1-integrin activating antibody (TS2/16) to cells cultured with liver injury serum significantly increased their adhesion to collagen, and prevented significant apoptosis. In conclusion, we have identified an important mechanism that underpins the failure of infused hepatocytes to engraft and survive in liver injury. Pretreating cells with an activating antibody can improve their engraftment and survival, indicating that serum from patients with liver injury exerts a defined nontoxic biological effect. This finding has important implications in the future of cellular transplantation for liver and other organ diseases. (HEPATOLOGY 2004;40:636–645.)