In order to investigate the contribution of the peripheral chemoreceptors to the susceptibility to post-hyperventilation apnea, we evaluated the time-course and magnitude of hypocapnia required to produce apnea at different levels of peripheral chemoreceptor activation produced by exposure to three levels of inspired PO₂. We measured the apneic threshold and the apnea latency in nine normal sleeping subjects in response to augmented breaths during normoxia (room air), hypoxia (SaO₂=78-80%) and hyperoxia (F_IO₂=50-52%). Pressure support mechanical ventilation in the assist mode was employed to introduce single or a variable number of consecutive, sigh-like breaths to cause apnea. The apnea latency was measured from the end-inspiration of the first augmented breath to the onset of apnea. It was 12.2±1.1 second (s)during normoxia, which was similar to the lung to ear circulation delay of 11.7s in these subjects. Hypoxia shortened the apnea latency (6.3±0.8s, p<0.05) while hyperoxia prolonged it (71.5±13.8s, p<0.01). The apneic threshold end-tidal PCO₂ (P_ETCO₂) was defined as the P_ETCO₂ at the onset of apnea. During hypoxia, the apneic threshold P_ETCO₂ was higher (38.9±1.7 mmHg, p<0.01) compared to normoxia (35.8±1.1 mmHg) while during hyperoxia, it was lower (33.0±0.8 mmHg, p<0.05). Furthermore, the difference between the eupneic P_ETCO₂ and apnea threshold P_ETCO₂ (P_ETCO₂) was smaller during hypoxia (3.0±1.0 mmHg, p<001) and greater during hyperoxia (10.6±0.8 mmHg, p<0.05) compared to normoxia (8.0±0.6 mmHg). Correspondingly, the hypocapnic ventilatory response slope to CO₂ below the eupneic P_ETCO₂ was increased by hypoxia (3.44±0.63 Lxmin^-1xmmHg^-1, p<0.05) and decreased by hyperoxia (0.63±0.04 Lxmin^-1xmmHg^-1,p<0.05) compared to normoxia (0.79± 0.05 Lxmin^-1xmm Hg^-1). These findings indicate that post-hyperventilation apnea is initiated by the peripheral chemoreceptors, and that the varying susceptibility to apnea during hypoxia versus hyperoxia is influenced by the relative activity of these receptors.