Summary Clearance of pathogens or tumor cells by antibodies traditionally requires both Fab and Fc domains of IgG. Here we show the Fc domain of IgG alone mediates recognition and clearance of herpes simplex virus (HSV1) infected cells. The human natural killer (NK) cell surface is naturally coated with IgG bound by its Fc domain to the Fcγ receptor CD16a. NK cells utilize the Fc domain of bound IgG to recognize gE, an HSV1-encoded glycoprotein that also binds the Fc domain of IgG but at a site distinct from CD16a. The bridge formed by Fc domain between the HSV1-infected cell and the NK cell results in NK cell activation and lysis of the HSV1-infected cell in the absence of HSV1-specific antibody in vitro, and prevents fatal HSV1 infection in vivo. This mechanism also explains how bacterial IgG-binding proteins regulate NK cell function, and may be broadly applicable to Fcγ receptor-bearing cells.