The responder cell frequency (RCF) of premature (< 1900 g birth weight) infants' blood lymphocytes, which proliferate in cultures stimulated by staphylococcal enterotoxin B, falls from 1:3400 to about 1:8000 during the first 2 wk of life. Term infants, in contrast, show no fall in RCF. The reduced RCF in the premature infants affected cells that make interferon-gamma more than cells making IL-4. The reduced RCF was accompanied by a fall in the fraction of V beta 3+ T cells that entered cell cycle in stimulated cultures. The RCF of premature infants' T cells was increased in cultures supplemented with irradiated monocytes from adults. Addition of IL-4 (but not IL-2, IL-6, or indomethacin) increased the RCF and fraction of cells entering cell cycle of the premature infants. The data suggest that postnatal environmental factors limit the ability of premature infants' monocytes to support a T-cell response to staphylococcal enterotoxin B in vitro and that this limitation is overcome by adding IL-4.