The role of antiviral antibodies in protection against neonatal herpes simplex virus (HSV) infection remains controversial. The relationship between neonatal and maternal antiHSV antibodies and disease presentation was analyzed in 47 babies. Of the neonates, 770/0 had localized and 23% had disseminated HSV infection. Antibody-dependent cellular cytotoxic (ADCC) antibodies were evaluated in comparison with HSV neutralizing antibodies. High maternal (>1:10⁴) or neonatal (>1:10³) anti-HSV ADCC antibody levels or high neonatal antiviral neutralizing levels (>1:20) were independently associated with an absence of disseminated HSV infection. Cochran-Mantel-Haenszel analysis demonstrated that ADCC levels were associated with disease status (P<.02) while controlling for the level of neutralizing antibody.