We hypothesized that chronic intermittent hypoxia (CIH) would induce a predisposition to apnea in response to induced hypocapnia. To test this, we used pressure support ventilation to quantify the difference in end-tidal partial pressure of CO₂ (PETCO₂) between eupnea and the apneic threshold ("CO₂ reserve"), as an index of the propensity for apnea and unstable breathing during sleep, both before and following up to 3 weeks' exposure to chronic intermittent hypoxia in dogs. CIH consisted of 25 seconds of PETO₂ = 35-40 Torr followed by 35 seconds of normoxia, and this pattern was repeated 60 times/hour, 7-8 hours/day for 3 weeks. The CO₂ reserve was determined during NREM sleep in normoxia 14-16 hours after the most recent hypoxic exposure. Contrary to our hypothesis, the slope of the ventilatory response to CO₂ below eupnea progressively decreased during CIH (control, 1.36±0.18; week 2, 0.94±0.12; week 3, 0.73±0.05 l·min-1·Torr^-1, P<0.05). This resulted in a significant increase in the CO₂ reserve relative to control (P<0.05) following both 2 and 3 weeks of CIH (control, 2.6±0.6; week 2, 3.7±0.8; week 3, 4.5±0.9 Torr). CIH also: a) caused no change in eupneic, air breathing PaCO₂; b) increased the slope of the ventilatory response to hypercapnia after 2 weeks but not after 3 weeks compared to control; and c) had no effect on the ventilatory response to hypoxia. We conclude that 3 weeks' CIH reduced the sensitivity of the ventilatory response to transient hypocapnia and thereby increased the CO₂ reserve, i.e., the propensity for apnea was reduced.