In the fumarylacetoacetate hydrolase deficient (Fah(-/-)) mouse, massive liver repopulation can be easily obtained after transplanted hepatocytes. Understanding the mechanisms of complete liver repopulation in Fah(-/-) mice will be useful for future clinical application. Here, we found that the endogenous hepatocytes in liver of Fah(-/-) mice undertook senescence during the time of tyrosinemia symptoms. Increase of senescent hepatocytes in Fah(-/-) mice provided proliferative advantage to the transplanted hepatocytes. Importantly, senescent hepatocytes upregulated the expression of extracellular matrix enzyme, contributing to degradation of extracellular matrix components and weakness of cell adhesion and connection. The liver exhibiting a loose architecture provided the space for the engraftment and expansion of transplanted hepatocytes. These findings underscore the underlying mechanisms of completed liver repopulation in Fah(-/-) mice. Senescence followed by loose hepatic parenchyma is a preconditioning for liver repopulation, which would be a promising strategy to achieve therapeutic liver repopulation in clinical settings. (C) 2019 Elsevier Inc. All rights reserved.