Antibody-dependent cellular cytotoxicity (ADCC) to cells infected with herpes simplex virus (HSV) is a mechanism of destruction of these cells by a combination of antiviral antibody and immunoglobulin Fc receptor-positive leukocytes. It has been well defined in vitro as a rapid lytic response utilizing minute amounts of IgG antibody. In vitro studies have shown ADCC restriction of the spread of virus. In vivo studies using adoptive transfer of human or murine ADCC effector cells plus antibody and ADCC-active, nonneutralizing F(ab1)2 antibody fragments or monoclonal antibodies have demonstrated the important role of this response in animal models of HSV infection. In humans, ADCC effector function and/or antibody levels have been associated with the outcome of infection, especially in immunocompromised patients and neonates. Reconstitution of this mechanism with appropriate antibodies or cytokines in high-risk hosts, with the resultant amelioration of severe HSV infection, will validate ADCC as a critical component of antiviral defense.