An increased susceptibility of the newborn to infection is well-recognized and it has been repeatedly observed in collected studies of serious bacterial infections of infants, i.e., sepsis, pneumonia and meningitis, that a preponderance of male infants exists over female. As early as the 1960s, we hypothesized that this increased susceptibility might be related to both age and gender related factors (Lancet 1:826, 1969). During the course of our studies of phagocytic cells in both the neonatal human and experimental animal, we have observed functional deficiencies related to both intrinsic factors, e.g., increased G-6PD liability, chemotactic deficiency, as well as extrinsic factors e.g., modulation of alveolar MØ by surfactant, PMNs by mucin. We have also reported a gender-related inverse relationship of PMN cyclooxygenase products (COP) i.e., (TxB2) with oxidative burst metabolites(OBM) i.e., (O2), with a greater production of OBM associated with a lowered synthesis of (COP) in the adult female, which we attributed to variations in levels of estrogens which are known to enhance phagocytic cell function (Mallery S. et al, J. Leuk. Biol. 40:133, 1986). Similar relationships may exist in the neonatal period where elevated estrogen levels occur in the early perinatal period in both male and females but only in male infants were peak elevated testosterone levels detected (Francis G.L. et al, Ann. Clin. Lab. Sci. 20:239, 1990). This could explain, in part, our recent findings of greater binding of bacteria (GBS, L. monocytogenes, and E. coli) to PMNs of female human neonates than males. Collectively, these studies provide a basis for gender and hormonal related modulation of the already compromised phagocytic cell system in the newborn.