Previous studies have established that leukocyte phagocytosis and intracellular killing are normal in term and low-birthweight newborns who are well. To determine the effect of stress or illness on newborn leukocyte function, the phagocytic and bactericidal activity of leukocytes from 40 sick newborns was compared with that of leukocytes from 12 newborns and 23 normal adults. To eliminate abnormal phagocytosis resulting from serum opsonic defects in newborn sera, pooled adult sera were used in all assays. Twenty-five of the 40 stressed newborns (63%) had decreased in vitro activity against either Staphylococcus aureus 502A or Escherichia coli, or both, compared with decreased activity in two of 12 well infants (17%) and in four of 23 adult controls (17%). The mean bactericidal activity (percentage of organisms killed after two hours) of leukocytes from stressed newborns against S. aureus (83% +/- 2 [SEM]) and E. coli. (87% +/- 4 [SEM]) was significantly less than in the combined well infant and adult control group (94% +/- 1 for S. aureus and 97% +/- .5 for E. coli). Although the more severely ill infants had an increased incidence of impaired antibacterial activity, the degree of impairment was not related to the severity of illness. No consistent relationship of decreased activity to birthweight, gestational age, age when studied, or specific diagnosis was seen. The leukocyte abnormality in stressed infants against S. aureus was principally a killing defect, while against E. coli both phagocytosis and killing were abnormal. This study indicates that a wide variety of neonatal disorders may affect one or more of the steps required for normal bacterial killing. The lability of leukocytic antibacterial function under stress is an additional mechanism for the newborn's increased susceptibility to infection.