Insulin-dependent diabetes has been shown to affect several aspects of receptor-mediated endocytosis. Since vanadate, a phosphate analogue, is known to exert insulin-like actions in target tissues, we studied the effects of vanadate on the endocytosis of the asialoglycoprotein receptor (ASGP-R) after its administration either in vivo (oral therapy) and/or in vitro by direct incubation of isolated hepatocytes with vanadate. The surface binding, internalization, and degradation of 3H-asialoorosomucoid (3H-ASOR), a prototype ligand of the ASGP-R, were decreased in diabetic rats by approximately 36.5%, 22.3%, and 12.9%, respectively. These values were normalized in diabetic rats treated by vanadate. Similarly, vanadate treatment normalized the biphasic dissociation of 3H-ASOR/ASGP-R complexes by restoring the rapid dissociation process. In contrast, vanadate treatment did not affect any of these endocytic parameters in normal rats. In vitro experiments were monitored by direct incubation of isolated hepatocytes with 10 mM vanadate. This incubation created an inhibitory effect on the endocytic parameters. In this work, we have demonstrated that vanadate treatment can reverse the alterations induced by diabetes on receptor-mediated endocytosis of the ASGP-R.