Passive administration of antiviral antibody has been assessed in animal models as a potential form of treatment for infections due to herpes simplex virus (HSY). Previous investigative work has demonstrated the beneficial effect of immune serum administered either before or after HSY infection of mice. In some studies the protective effect of antibody was abrogated in the absence of T lymphocytes, an observation suggesting that cellular effector mechanisms may be necessary for antibody efficacy. In the present study of a mouse model of encephalitis caused by HSY type 2, a 0.5-ml dose ofhuman immunoglobulin (1,250 mg of immunoglobulin G/kg of body weight) prepared at pH 4.25 for intravenous administration reduced mortality and prolonged survival when administered by intraperitoneal injection 24 hr before or up to 8 hr after intranasal viral challenge. The serum titer of HSY-neutralizing antibody and the response to therapy were dose dependent. Clinical trials of passive immunotherapy for severe HSY infections may be warranted.