To examine whether hepatic plasma membrane receptors for asialoglycoproteins are replaced or reutilized during endocytosis, receptors on the surface of isolated hepatocytes were uniquely labeled by neuraminidase treatment. This enzyme abolishes binding of asialo-orosomucoid, a galactose-terminated glycoprotein, and restricts the ligand specificity of the cell surface receptor protein to N-acetylgalactosamine-terminated glycoproteins such as desialylated ovine submaxillary mucin. Although a much larger intracellular pool of apparently identical receptor protein is unaffected by neuraminidase, endocytosis of asialo-orosomucoid does not occur in neuraminidase-treated cells, while endocytosis of desialylated ovine submaxillary mucin is unaffected. Endocytosis of desialylated ovine submaxillary mucin, in amounts far exceeding cell surface binding capacity, is not a consequence of replacement of neuraminidase-treated surface receptor by intracellular receptor. Binding and endocytosis of asialoglycoproteins appear, therefore, to be maintained through a continuous reutilization of plasma membrane receptors rather than through their replacement from an intracellular receptor pool.