To determine the involvement of different hepatocyte populations in response to periportal injury, the restitutive response to allyl alcohol (AA) injury was examined. Adult female Sprague-Dawley rats were injected intra-peritoneally (IP) with 0.62 mmol/kg AA, killed at 6, 9, 12, 33, 57, 81, and 153 hours after injection, and the livers were examined for injury and for restitutive proliferation by histology, autoradiography, and immunohisto-chemistry to detect alpha-fetoprotein (AFP), glutathi-one-s-transferase-p (GST-p), desmin, leukocyte common antigen, albumin, and monoclonal antibodies to liver cells: OV-6, H-4, and T-6. AA produces variable periportal liver necrosis predominantly at 6 to 12 hours. Proliferation of hepatocytes throughout the hepatic cord is seen early after injury in nonnecrotic areas: predominantly in zone II, but also in zones I and III, including some cells adjacent to the central vein. Within 2 to 3 days the necrotic zones are filled with small cells and by 1 week the liver architecture is essentially restored. During the active restitutive reaction from the immediate periportal rim the following cell phenotypes are seen: null cells: ± (AFP+, OV-6-, GST-p—) cells ± (AFP—, OV-6+, GST-p+) cells →large (AFP—, OV-6–, GST-p—, H-4+) liver cells. Albumin staining was negative. We conclude that restitutive proliferation of periportal necrosis induced by AA appears to be accomplished by proliferation of intraportal (?stem) cells whose progeny differentiate and eventually repopulate the necrotic zone.