Antibodies were used to quantify seven domain-specific integral proteins of the rat hepatocyte plasma membrane during rat liver regeneration in response to two-thirds hepatectomy. Quantitative immunoblotting revealed that a subset of the plasma membrane proteins exhibited transient 30-70% decreases in relative concentration during the period of hepatocyte proliferation. The list of affected proteins included at least one representative from each of the plasma membrane domains: the apical protein HA 4, the lateral protein HA 321, and the basolateral receptors for epidermal growth factor and asialoglycoproteins. In contrast, the relative concentrations of three other plasma membrane proteins, the basolateral protein CE 9 and the two apical proteins dipeptidylpeptidase IV and aminopeptidase N, remained unchanged throughout liver regeneration. The decreases in the relative concentrations of the plasma membrane proteins were observed even when the synthesis of hepatocyte DNA was blocked by hydroxyurea, suggesting that the signalling for these two delayed consequences of two-thirds hepatectomy occurred along parallel, dependent pathways. Pulse and pulse-chase metabolic radiolabeling studies revealed that the decreases in the concentrations of the PM proteins were accomplished through protein-selective decreases in the rates of synthesis of the high-mannose precursors of the affected proteins, but not through the accelerated degradation of the mature plasma membrane proteins.