Rationale: Periodic occlusion of the upper airway in patients with obstructive sleep apnea (OSA) leads to chronic intermittent hypoxia, which is known to increase the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans. Objectives: To determine i) whether four days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress, and ii) the strength of the association between oxidative stress and AHVR. Methods: Following two normoxic control days (Day -4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1-4) of intermittent hypoxia 6 hours per day. Measurements: AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring -tocopherol, total vitamin C and antioxidant enzymatic activities. Main Results: Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid and vitamin C whereas antioxidant enzymatic activities and -tocopherol were unchanged. Furthermore, there were strong correlations between the changes in AHVR and DNA oxidation (r=0.88, p=0.002). Conclusions: Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species (ROS) without a compensatory increase in anti-oxidant activity. Furthermore, this human study shows that ROS over-production modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with OSA.