Neonatal herpes simplex virus (HSV) infection produces severe disease with unacceptable morbidity and mortality with current antiviral therapies. The effect of therapy with passive anti-HSV antibody and acyclovir was evaluated using a guinea pig model of neonatal HSV. Newborn animals were inoculated intranasally and treated with acyclovir (60 mg/kg/day) or antibody (or both), beginning on days 0, 2, or 3 after HSV-2 inoculation. Acyclovir alone was effective only when begun on day 0, and antibody alone was effective when begun on or before day 2. Only combination therapy was effective on day 3, reducing mortality from 82% (14/17) in controls to 44% (7/16; P < .05). Combined therapy also significantly reduced the duration of skin, eye, and mouth disease and respiratory symptoms but not recurrent disease. These data suggest that addition of antibody therapy to acyclovir may improve the outcome of neonatal HSV disease.