The role of antiviral antibodies in protection against neonatal herpes simplex virus (HSV) infection remains controversial. The relationship between neonatal and maternal anti-HSV antibodies and disease presentation was analyzed in 47 babies. Of the neonates, 77% had localized and 23% had disseminated HSV infection. Antibody-dependent cellular cytotoxic (ADCC) antibodies were evaluated in comparison with HSV neutralizing antibodies. High maternal (greater than 1:10(4)) or neonatal (greater than 1:10(3)) anti-HSV ADCC antibody levels or high neonatal antiviral neutralizing levels (greater than 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 less than .02) while controlling for the level of neutralizing antibody.