We examined, in 32 normal adults, the effect of hypoxia on the sensation of dyspnea during hypercapnic ventilatory response (HCVR). The tests were conducted under two different levels of inspiratory O2 content, either hyperoxia (PETO2 greater than 150 Torr) or hypoxia (PETO2 50-55 Torr), with simultaneous assessment of dyspnea sensation by visual analogue scaling (VAS). The sensation was evaluated either in relation to VE standardized by predicted MVV (the slope of VAS-VE regression line or VAS at VE 40%) or in relation to PETCO2 (the slope of VAS-PETCO2 line or VAS at PETCO2 55 Torr). Concomitant hypoxia significantly enhanced both the mean value of delta VE/delta PETCO2 and that of delta P0.1/delta PETCO2. The sensation of dyspnea did not differ between the two conditions when it was evaluated in relation to ventilation, whereas it was markedly greater during hypoxic HCVR when it was evaluated in relation to PETCO2. The hypoxic augmentation of the sensation, compared at PETCO2 55 Torr, could be explained by increase of the motor output from the respiratory center, since it was positively correlated with the relative change of VE, VTTI, and delta P0.1/delta PETCO2 (r = 0.70, p less than 0.0001; r = 0.63, p less than 0.0001; r = 0.40, p less than 0.05, respectively). From these findings, we conclude that hypoxia does not have a direct dyspnogenic effect, at least in normal subjects.