Exercise performance during an acute exposure to hypoxia is impaired via a reduction in arterial oxygen content (Fulco et al. 1998). These decrements in performance during moderate hypoxia (FIO2 0.13-0.15) are largely attributed to peripheral mechanisms (Amann et al. 2006) and in severe hypoxia (FIO2 < 0.115) to a hypoxia-sensitive ‘central’ component via brain hypoxia (Subudhi et al. 2009). Central processing of the perception of effort is important in the determination of exercise intensity. The subjective rating of perceived exertion, termed RPE, is a psychophysiological concept (Morgan 1994) that centrally integrates perceptual, peripheral, experiential, and environmental sensory cues (Hampson et al. 2001). The purpose of this study was to determine the primary cues regulating perceived effort and exercise performance using an RPE-clamp protocol in severe and moderate hypoxia. Eight male participants (26 ± 6 y, 76.3 ± 8.6 kg, 51.4 ± 8.0 mL.kg-1.min-1 VO2max) completed three exercise trials in environmental conditions of severe hypoxia (FIO2 0.114), moderate hypoxia (FIO2 0.152) and normoxia (FIO2 0.202). They were instructed to continually adjust their power output to maintain a perceived effort (RPE) of 16, exercising until power output declined to 80 % of the peak 30-s power output achieved. Expired gases were measured breath-by-breath to assess oxygen consumption (VO2), minute ventilation, breathing frequency, tidal volume and end-tidal oxygen (PETO2), and carbon dioxide (PETCO2). Heart rate, oxygen saturation (SPO2) and muscle tissue oxygenation (NIRS) were also measured. Exercise time was reduced (severe hypoxia 428 ± 210 s; moderate hypoxia 1044 ± 384 s; normoxia 1550 ± 590 s) according to a reduction in FIO2 (P <0.05). The rate of oxygen desaturation during the first 3-min of exercise was accelerated in severe hypoxia (-5.3 ± 2.8 %.min-1) relative to moderate hypoxia (-2.5 ± 1.0 %.min-1) and normoxia (-0.7 ± 0.3 %.min-1). Muscle tissue oxygenation did not differ between conditions (P >0.05). Minute ventilation increased at a faster rate according to a decrease in FIO2 (severe hypoxia 27.6 ± 6.6; moderate hypoxia 21.8 ± 3.9; normoxia 17.3 ± 3.9 L.min-1). PETCO2was reduced in severe hypoxia relative to normoxia (P = 0.015). Moderate to strong correlations were identified between breathing frequency (r = -0.718, P < 0.001), blood oxygen saturation (r = 0.611, P = 0.002) and exercise performance. Performance time was diminished when exposed to decreasing FIO2. Increases in breathing frequency and blood oxygen desaturation during the early stages of exercise were correlated with reductions in task performance. However, oxygen extraction at the muscle appeared to be tightly regulated to match the metabolic demand. Therefore, the primary cues for determining perceived effort relate to progressive arterial hypoxemia and increases in ventilation.