In a previous paper, we reported a ligand-induced modulation of the asialoglycoprotein receptors on HepG2 cells whereby these receptors were rendered functionally inert while remaining immunologically intact on the plasma membrane. At that time, it was speculated that the loss in receptor-binding ability was a direct result of a concomitant decrease in cell surface sialic acid residues. Experiments designed to test that hypothesis are presented. The results revealed: 1) an identical response in binding activity and sialic acid content in cells subjected to minimal exposure to neuraminidase; 2) a parallel and synchronous recovery of both parameters following modulation; 3) an invariant binding of high affinity ligands, and 4) the ability of galactose oxidase to restore, at least partially, the cell's ability to bind asialoglycoprotein. These results indicate that ligand-induced surface hyposialylation directly diminishes expression of the asialoglycoprotein receptor.