A recombinant human anti-herpes simplex virus monoclonal IgG1antibody and the corresponding Fab and F(ab′)2fragments were tested for efficacy in preventing vaginal transmission of HSV-2 infection in a well-established mouse model for genital herpes. IgG1, Fab, and F(ab′)2were approximately equally protective; vaginal delivery of 1–5 ng provided approximately 50% protection, and vaginal delivery of 400 ng completely protected mice from genital herpes infection (P< 0.001). These results suggest that topical applications of human monoclonal antibodies may be useful in developing new methods for preventing sexually transmitted disease.