The temporal sequence of .alpha.-fetoprotein appearance in serum was determined in necrogenic and nonnecrogenic liver injury. The carcinogens ethionine, thioacetamide and CCl4 were used to intoxicate male and female rats for evaluating serum enzyme levels, mitotic indices and morphological reflections of impairment. Thioacetamide- and CCl4-induced cell death preceded the mitotic wave in residual hepatocytes, and, in the case of both agents, this intoxicant-mediated necrosis preceded the emergence of .alpha.-fetoprotein. Although there was no evidence of cell destruction or significant mitotic activity in ethionine poisoned animals, serum .alpha.-fetoprotein levels progressively increased. The temporal sequence of .alpha.-fetoprotein synthesis and/or release and cellular reorganization for regeneration suggests that reappearance of the protein macromolecule is an expression of the altered phenotype observed during the step-down phase of liver regeneration.