Rationale: The mechanisms by which chemoreceptors process carbon dioxide stimuli are poorly understood. Recent in vitro studies suggest a role of reactive oxygen species in central carbon dioxide chemoreception. Objectives: We tested the hypothesis that antioxidant treatment modulates the ventilatory response to carbon dioxide in healthy humans either during unloaded breathing or after strenuous resistive breathing. Methods: In the first experiment of this randomized, double-blind, placebo-controlled study, 14 healthy males completed hyperoxic carbon dioxide rebreathing, received either antioxidants (vitamins E, A and C for two months, allopurinol, and N-acetylcysteine) (n=7) or placebo (n=7), and repeated rebreathing three months later. In the second experiment, 18 healthy males completed a series of rebreathing tests before and after strenuous resistive breathing. Subjects repeated the same protocol three months later after had received antioxidants (n = 9) or placebo (n = 9). Main Results: Following antioxidants, the sensitivity of the ventilatory (minute ventilation) response to carbon dioxide increased (mean [±SEM], 3.2±0.5 vs. 1.7±0.4 L/min/mmHg, p<0.001). Antioxidants also increased the sensitivity to carbon dioxide before and at 5, 30 and 120 minutes following resistive breathing (p=0.01). This effect was entirely due to increased tidal volume. Antioxidants did not influence the breathing pattern during resting breathing or the rapid shallow breathing response to carbon dioxide at 5 minutes following resistive breathing. Conclusions: Antioxidants by augmenting the tidal volume increase the sensitivity of the ventilatory response to carbon dioxide either during unloaded breathing or after resistive breathing.