Neonates have lower plasma cytokine levels of IL-3, IL-4, IL-10, and IL-13 than adults. Cord blood monocyte derived macrophages (MDM) are more suseptible to infection by HIV-1 than adult MDM (Ho WZ. J Virol. 66:573, 1992). Infection of monocytes with HIV-1 induces dysregulation of cytokines which may play a vital role in HIV-1 pathogenesis. Our hypothesis is that these cytokines may play an important role in HIV-1 infection of cord blood MDM in vitro. We studied the effect of IL-3, IL-4, IL-10, and IL-13 on HIV-1 infection of cord blood MDM from 4 healthy full term infants (HIV negative). Monocytes were isolated and cultured for 10-14 days, then infected with HIV-1 BAL strain. The cytokines were added to the cells before, during, and on successive days after infection. Supernatants were collected in triplicate on successive days for reverse transcriptase analysis by radioimmunoassay. HIV-1 viral replication was inhibited with IL-3 by 79% (p < 0.025); with IL-4 by 87-91% (p < 0.02); with IL-10 by 83-85% (p < 0.05); and with IL-13 by 25-95% (p < 0.05). Thus, increases in IL-3, IL-4, IL-10, and IL-13 inhibit HIV-1 replication in vitro. We speculate that low levels of cytokines that are present in newborns may predispose infants born to HIV-1 infected mothers to acquiring HIV-1 infection. Upregulation of these cytokines may help decrease perinatal transmission of HIV-1 in newborn infants.