The liver is of central importance in the metabolism of essential and toxic metals such as cadmium (Cd). Cd pretreatment suppressed the regenerative capacity of hepatocytes, which normally occurs 24 hr after partial hepatectomy, due to the inhibition of the activity of the enzyme thymidine kinase. The effect of hepatic stimulator substance (HSS) administration (10, 20, and 40 mg protein/kg body weight) on hepatocyte proliferation was investigated in Cd-pretreated partially hepatectomized rats. HSS administration partly restored the suppressed hepatocyte DNA biosynthesis in Cd-pretreated partially hepatectomized rats. The hepatocyte mitotic activity and the percentage of proliferating cell nuclear antigen-positive nuclei were in accordance with the liver proliferative status. The administration of HSS did not affect in a statistically significant manner the activity of the enzyme thymidine kinase in Cd-pretreated partially hepatectomized rats. It is suggested that the administration of HSS ameliorates the diminished hepatocyte regenerative response to partial hepatectomy in this model of acute liver injury, due to Cd intoxication.