Neonatal hypoxia alters development of the hypoxic ventilatory response in rats and other mammals. Here we demonstrate that neonatal hypoxia impairs the hypoxic ventilatory response in adult male, but not adult female, rats. Rats were raised in 10% O₂ for the first postnatal week, beginning within 12 h after birth. Subsequently, ventilatory responses were assessed in 7-9 wk old unanesthetized rats via whole-body plethysmography. In response to 12% O₂, male rats exposed to neonatal hypoxia increased ventilation less than untreated control rats (35.2±7.7% S.E.M. vs. 67.4±9.1%, respectively; P=0.01). In contrast, neonatal hypoxia had no lasting effect on hypoxic ventilatory responses in female rats (67.9±12.6% vs. 61.2±11.7% increase in hypoxia-treated and control rats, respectively; P>0.05). Normoxic ventilation was unaffected by neonatal hypoxia in either gender at 7-9 wks of age (P>0.05). Since we hypothesized that neonatal hypoxia alters the hypoxic ventilatory response at the level of peripheral chemoreceptors or the central neural integration of chemoafferent activity, integrated phrenic responses to isocapnic hypoxia were investigated in urethane-anesthetized, paralyzed and ventilated rats. Phrenic responses were unaffected by neonatal hypoxia in rats of either gender (P>0.05), suggesting that neonatal hypoxia-induced plasticity occurs between the phrenic nerve and the generation of airflow (e.g., neuromuscular junction, respiratory muscles or respiratory mechanics) and is not due to persistent changes in hypoxic chemosensitivity or central neural integration. The basis of gender differences in this developmental plasticity is unknown.