This study examines the effects of mutations at and in the vicinity of tyrosine 992 of the epidermal growth factor receptor (EGFr) on epidermal growth factor- (EGF-) stimulated internalization of the receptor. Two regions of the EGFr adjacent to this domain have been defined previously as internalization domains. The present work shows that the mutation of negatively charged amino acid residues near Tyr992 to their uncharged analogues increases the rate of EGF receptor internalization. In addition, the conversion of Tyr992, which is an EGFr ligand-induced autophosphorylation site, to phenylalanine also increases the rate of receptor internalization. However, the mutation of Tyr992 to a glutamate residue does not alter the receptor internalization rate. In addition, the truncation of the EGFr at glutamate 996 reduces the internalization rate by half. This result confirms previous reports that residues immediately C-terminal to Glu996 are necessary to allow the normal rate of ligand-induced receptor endocytosis. The data suggest that negative charge in the vicinity of Tyr992, and potentially the phosphorylation of the EGFr at Tyr992, reduces the rate of ligand-induced receptor endocytosis. This reduction in internalization rate increases the lifetime of the activated EGFr in the plasma membrane by about 70%, thus suggesting that phosphorylation of Tyr992 acts to increase the signaling capacity of the EGF receptor even as it directly acts as an SH2 binding site.