Cellular proliferation and tissue remodeling are central to the regenerative response after a toxic injury to the liver. To explore the role of plasminogen in hepatic tissue remodeling and regeneration, we used carbon tetrachloride to induce an acute liver injury in plasminogen-deficient (Plg^o) mice and nontransgenic littermates (Plg⁺). On day 2 after CCl₄, livers of Plg⁺ and Plg^o mice had a similar diseased pale/lacy appearance, followed by restoration of normal appearance in Plg⁺ livers by day 7. In contrast, Plg^o livers remained diseased for as long as 2.5 months, with a diffuse pale/lacy appearance and persistent damage to centrilobular hepatocytes. The persistent centrilobular lesions were not a consequence of impaired proliferative response in Plg^o mice. Notably, fibrin deposition was a prominent feature in diseased centrilobular areas in Plg^o livers for at least 30 days after injury. Nonetheless, the genetically superimposed loss of the Aα fibrinogen chain (Plg^o/Fib^o mice) did not correct the abnormal phenotype. These data show that plasminogen deficiency impedes the clearance of necrotic tissue from a diseased hepatic microenvironment and the subsequent reconstitution of normal liver architecture in a fashion that is unrelated to circulating fibrinogen.