To determine the effects of endotoxemia on the neonatal ventilatory response to hypoxia, 17 chronically instrumented and unanesthetized newborn piglets (</=7 d) were studied before and 30 min after the administration of Escherichia coli O55:B5 endotoxin (n = 8) or normal saline (n = 9). Minute ventilation, oxygen consumption, heart rate, arterial blood pressure, and blood gases were measured during normoxia and 10 min of hypoxia (fraction of inspired oxygen, 0.10). Basal ventilation was not modified by E. coli endotoxin infusion (mean +/- SE, 516 +/- 49 versus 539 +/- 56 mL/min/kg), but the ventilatory response to hypoxia was markedly attenuated at 1 min (955 +/- 57 versus 718 +/- 97 mL/min/kg, p < 0.002, saline versus endotoxin) and at 10 min (788 +/- 51 versus 624 +/- 66 mL/min/kg, p < 0.002). A larger decrease in oxygen consumption was observed during hypoxia and endotoxemia (6.3 +/- 2.8 versus 18.3 +/- 2.7%, p < 0.03, pre- versus post-endotoxin). A significant correlation was demonstrated between the changes in minute ventilation and oxygen consumption with hypoxia during endotoxemia (r = 0.9, p < 0.002). The ventilatory response to hypoxia was not modified by the saline infusion. These data show a significant attenuation in the ventilatory response to hypoxia during E. coli endotoxemia. This decrease in ventilation was associated with a significant decrease in the metabolic rate during hypoxia and endotoxemia.