The role of antibody and, in particular, antibody-dependent cellular cytotoxicity (ADCC) antibodies, in preventing or reducing the severity of infection with herpes simplex virus (HSV) in neonates is controversial. We have shown that human and murine neonates, in contrast with adults, are relatively deficient in ADCC leukocyte effector cell function. In an adoptive transfer model, the combination of ADCC-active human leukocytes and antibody to HSV could protect neonatal mice from lethal infection with HSV. Use of cells defective in ADCC function (e.g., from human neonates or patients with the CD11,18 deficiency in cell surface adhesive integrin) could not provide protection in this model. Finally, in human neonates the level of ADCC antibody at the time of infection with HSV was associated with severity of illness. Thus, ADCC is an important host defense against neonatal infection with HSV.