Although pharyngeal muscles respond robustly to increasing Pco 2 during wakefulness, the effect of hypercapnia on upper airway muscle activation during sleep has not been carefully assessed. This may be important, because it has been hypothesized that CO2-driven muscle activation may importantly stabilize the upper airway during stages 3 and 4 sleep. To test this hypothesis, we measured ventilation, airway resistance, genioglossus (GG) and tensor palatini (TP) electromyogram (EMG), plus end-tidal Pco 2(Pet CO2 ) in 18 subjects during wakefulness, stage 2, and slow-wave sleep (SWS). Responses of ventilation and muscle EMG to administered CO2(Pet CO2 = 6 Torr above the eupneic level) were also assessed during SWS ( n = 9) or stage 2 sleep ( n = 7). Pet CO2 increased spontaneously by 0.8 ± 0.1 Torr from stage 2 to SWS (from 43.3 ± 0.6 to 44.1 ± 0.5 Torr, P < 0.05), with no significant change in GG or TP EMG. Despite a significant increase in minute ventilation with induced hypercapnia (from 8.3 ± 0.1 to 11.9 ± 0.3 l/min in stage 2 and 8.6 ± 0.4 to 12.7 ± 0.4 l/min in SWS, P < 0.05 for both), there was no significant change in the GG or TP EMG. These data indicate that supraphysiological levels of Pet CO2 (50.4 ± 1.6 Torr in stage 2, and 50.4 ± 0.9 Torr in SWS) are not a major independent stimulus to pharyngeal dilator muscle activation during either SWS or stage 2 sleep. Thus hypercapnia-induced pharyngeal dilator muscle activation alone is unlikely to explain the paucity of sleep-disordered breathing events during SWS.