Young adult mice infected with 3 X 10(6) plaque-forming units of herpes simplex virus type 2 (HSV-2) died within 9 to 12 days after spread of the virus from the sites of infection to the spinal cord and brain. Administration of HSV-2-neutralizing antisera prepared in syngenic mice or in rabbits inhibited spread of the virus from the footpad of infected animals and prevented death. A single intraperitoneal inoculum of antiserum (virus-neutralizing titer of 1:128) was effective in protecting mice when the antiserum was given at 8 to 48 h, but not at 72 h, after virus inoculation. Immune sera absorbed with HSV-2-infected cells no longer protected mice from subcutaneous infection, whereas absorption with noninfected cells had no effect. Thus, HSV-2-specific antibodies appeared to be responsible for the protection observed. If the mice were given a sublethal dose of irradiation (390 rads) at 24 h before antibody transfer, protection was no longer obtained. This suggested that the mechanism of protection probably was not solely due to in vivo neutralization of virus, but required the participation of a radiosensitive component which has not yet been defined.