To characterize cellular responses during hepatic regeneration, we examined 13 explant livers and 5 liver allografts by immunohistochemistry for cytokeratin 7, HepPar1, CD68, α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen as well as reticulin and Masson-trichrome staining. Within a week after liver damage, elongated CD68-positive cells were detected along the border of necrotic area. The number of α-SMA-positive cells was slightly increased along the sinusoids. Ductular proliferation or fibrosis was negligible. After one or two weeks, the size and number of CD68-positive cells were markedly increased.α-SMA-positive cells increased in number within lobules and portal tracts. Ductular proliferation occurred predominantly at the limiting plate or along the border of necrotic areas. After one month, necrotic parenchyma was replaced by many ductules, CD68-positive cells, α-SMA-positive cells. Nodules of regenerating hepatocytes and irregular fibrosis were diffusely present. Other nonparenchymal cells were not significantly changed. These observations indicate that chronological interaction between nonparenchymal and parenchymal cells occur during the course of human hepatic regeneration and suggest extensive porto-periportal fibrosis more than a few months after the onset of fulminant hepatitis is a major indicator of chronic functional impairment necessitating liver transplantation.