The odds risk of vertical transmission of human immunodeficiency virus (HIV) to preterm infants is almost four times that of term infants and may relate to maternal and neonatal factors. We characterized the competence of early nonspecific cellular immunity, namely natural killer cytotoxicity (NKC) and antibody-dependent cellular cytotoxicity (ADCC), of peripheral blood mononuclear cells (PBMC) from preterm (n = 20) and term neonates (n = 28) versus adult controls against a T cell line infected with the human T cell lymphotrophic virus-III(B) using a chromium-51 release assay. PBMC from term neonates exhibited levels of NKC activity equal to adults against HIV-infected targets, yet the NKC capacity of preterm neonatal PBMC was significantly diminished. The ADCC activity of both term and preterm neonatal PBMC against HIV-infected targets was significantly less than that of adult PBMC. Overnight stimulation of a subset of samples with IL-12 augmented the NKC activity of both infant groups and adults, whereas the ADCC activity remained unchanged. These findings demonstrate that term neonates are deficient in ADCC against HIV-infected targets, whereas preterm infants are deficient in both NKC and ADCC, which may relate, in part, to the increased risk of transmission of HIV with preterm delivery. In addition, IL-12 has the potential to augment both term and preterm neonatal antiviral defense.