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Neither human immune globulin nor human mononuclear leukocytes (containing lymphocytes and monocytes) from herpes simplex virus (HSV) seronegative adult donors could protect infant C57BL/6 mice from a lethal HSV infection. In contrast, a combination of 5 X 10(6) leukocytes and a subneutralizing dose of antibody protected the mice. Leukocytes (5 X 10(6) or 1 X 10(7)) from neonatal humans and antibody could not mediate this protection. This is the first correlation between defective human neonatal leukocyte antibody-dependent cellular cytotoxicity (ADCC) in vitro and defective human neonate leukocyte-antibody protection against HSV infection in vivo in mice.