New Findings: What is the central question of this study? The central question of this study was to investigate the interaction of mild exposures to O2 and CO2 on chemoreflex control of SNA and the modulation of lung volume and respiratory phase on this interaction. What is the main finding and its importance? We demonstrate that the synergistic interaction of oxygen- and carbon dioxide-chemosensitive control of the sympathetic nervous system with hypoxia and hypercapnia exists at very mild excitatory stimuli, is significantly overridden by lung inflation and does not extend to inhibitory modulation by hypocapnia in healthy subjects. These findings demonstrate the important inhibitory modulation of sympathetic nerve activity by lung inflation mechanisms in healthy individuals even in the presence of strong sympathoexcitatory stimuli. We hypothesized that simultaneous stimulation of O2- and CO2-sensitive chemoreflexes produces synergistic activation of the sympathetic nervous system and that this effect would be most apparent at low lung volume (expiratory) phases of respiration. Each subject (n = 11) breathed 16 gas mixtures in random order: a 4 × 4 matrix of normoxic to hypoxic (8, 12, 16 and 21% O2) combined with normocapnic to hypercapnic gases (0, 2, 4 and 6% CO2). Tidal volume, arterial pressure, heart rate and muscle sympathetic nerve activity (MSNA) were measured continuously before and while breathing each gas mixture for 2 min. Changes in MSNA were determined for each gas mixture. The MSNA was subdivided into low and high lung volume and respiratory phases to investigate further modulation by components of normal respiratory phase. Both hypoxia and hypercapnia increased mean MSNA independently. Mean and low lung volume MSNA increased exponentially with increasing levels of combined hypoxia and hypercapnia and resulted in a significant interaction (P < 0.01). In contrast, MSNA during the high lung volume phase of respiration never increased significantly (P > 0.4). Similar but less pronounced effects were found for expiratory and inspiratory phases of respiration. These effects created marked respiratory periodicity in MSNA at higher levels of combined hypoxia and hypercapnia. Finally, the response to hypoxia was not affected by hypocapnia, suggesting that the interaction occurs only during excitatory chemosensitive stimuli. These data indicate that hypoxia and hypercapnia interact to elicit synergistic sympathoexcitation and that withdrawal of sympathoinhibitory effects of lung inflation exaggerates this chemoreflex interaction.