Varicella-zoster virus (VZV) encodes a functional cell membrane Fc receptor called glycoprotein gE. VZV gE resembles other mammalian cell membrane receptors, such as the mammalian Fc receptor. In further analyses by transient transfection, the cellular trafficking of VZV gE was compared to other cell surface receptors. VZV gE was shown to undergo endocytosis from the cell membrane when visualized by laser scanning confocal microscopy. The endocytosis and trafficking pathway of VZV gE followed closely the pathway defined for the human transferrin receptor. Receptor-mediated endocytosis of VZV gE was dependent on a YAGL motif in its cytoplasmic tail. In addition, VZV gE underwent receptor-mediated endocytosis when it bound the Fc portion of immunoglobulin. Thus, this detailed study of VZV gE cellular trafficking has revealed potential roles for gE during viral infection.