Purpose: The purpose of this study was to determine the primary cues regulating perceived effort and exercise performance using a fixed-RPE protocol in severe and moderate hypoxia. Methods: Eight male participants (26 ± 6 years, 76.3 ± 8.6 kg, 178.5 ± 3.6 cm, 51.4 ± 8.0 mL kg − 1 min − 1 V˙ O 2max ) completed three exercise trials in environmental conditions of severe hypoxia (F I O 2 0.114), moderate hypoxia (F I O 2 0.152), and normoxia (F I O 2 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. Results: Exercise time was reduced (severe hypoxia 428 ± 210 s; moderate hypoxia 1044 ± 384 s; normoxia 1550 ± 590 s) according to a reduction in F I O 2 (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 F I O 2 (severe hypoxia 27.6 ± 6.6; moderate hypoxia 21.8 ± 3.9; normoxia 17.3 ± 3.9 L min − 1 ). 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. Conclusions: The primary cues for determining perceived effort relate to progressive arterial hypoxemia and increases in ventilation.