Monoclonal antibodies secreted by six hybridomas and recognizing antigenic sites on glycoproteins gC, gAB, gD, gE, and gF of herpes simplex virus type 2 were examined for their ability to protect BALB/c mice from lethal infection by the virus. Administration of monoclonal antibodies to individual glycoproteins intraperitoneally 3 h before footpad challenge with 10 times the 50% lethal dose of virus protected between 35 and 75% of the mice, except for one of two monoclonal antibodies recognizing antigens on gC. The antibodies did not neutralize virus in vitro and protected A/J mice deficient in the fifth component of complement as efficiently as complement-sufficient BALB/c mice. A good correlation was found between protection and titers of monoclonal antibodies assessed by antibody-dependent cell-mediated cytolysis. The results indicate that any of the glycoproteins can serve as antigens for a protective immune response. In addition, the data are compatible with protection being mediated by an antibody-dependent cell-mediated cytolysis mechanism.