The hypoxic ventilatory response during hypocapnia has been studied with divergent results. We used volume-cycled ventilation in spontaneously breathing normal subjects to study their hypoxic ventilatory response under conditions of stable hypocapnia. Subjects were studied at three different levels of end-tidal (partial) carbon dioxide pressure (PETCO2), eucapnia and 6 and 12 mm Hg below eucapnia (mild and moderate hypocapnia, respectively). The response to hypoxia was assessed by changes in muscle pressure output (Pmus) and respiratory rate. Compared with the Pmus response at eucapnia (0.53 +/- 0.59 cm H2O/percentage oxygen saturation [% O2sat]), the response at mild hypocapnia was attenuated (0.26 +/- 0.33 cm H2O/% O2sat), whereas the response at moderate hypocapnia was negligible (0.003 +/- 0.09 cm H2O/% O2sat). Similar reductions were seen with the respiratory rate (eucapnia, 0.17 +/- 0.2 breaths/minute/% O2sat; mild hypocapnia, 0.11 +/- 0.11 breaths/minute/% O2sat; moderate hypocapnia, 0.01 +/- 0.06 breaths/minute/% O2sat). The Pmus and respiratory rate responses at the three levels of PETCO2 were significantly different (p < 0.05, analysis of variance). The responses at moderate hypocapnia were not significantly different from zero. We conclude that when apnea occurs under conditions in which central PCO2 is well below the CO2 setpoint, subjects are at risk of developing dangerous hypoxemia due to absence of a hypoxic ventilatory response.