The in vivo protective role of herpes simplex virus (HSV-1)-specific antibody was analyzed using monoclonal antibodies (MAbs) reactive with discrete antigenic sites on glycoproteins B, C, and D (gB, gC, gD) in the murine zosteriform spread model of HSV-1. All ofthe anti-gC and anti-gD MAbs, and one of four anti-gB MAbs (B6) were protective. The in vitro abilities of the MAbs to neutralize HSV-1 and mediate antibody-dependent cellular cytotoxicity (ADCC) against HSV1- infected cells wereexamined as potential mechanistic correlates to in vivoprotection. All animals given MAbs at high ADCC unit doses were protected. Some but not all mice given MAbs at high ADCC unit doses were protected. These studies designate specific epitopes recognized by protective antibodies and indicate that protection from the neurologic spread of HSV may be related to neutralization, ADCC, or both. The actual contribution of ADCC and neutralization to in vivo antibody-mediated protection remains unclear.