Purpose: We explored the effects of the sense of effort and accompanying perceptions of peripheral discomfort on self-selected cycle power output under two different inspired O2 fractions. Methods: On separate days, eight trained males cycled for 5 min at a constant subjective effort (sense of effort of '3' on a modified Borg CR10 scale), immediately followed by five 4-s progressive submaximal (sense of effort of "4, 5, 6, 7, and 8" 40 s between bouts) and two 4-s maximal (sense of effort of "10" 3 min between bouts) bouts under normoxia (NM: fraction of inspired O2 [FiO2] 0.21) and hypoxia (HY: [FiO2] 0.13). Physiological (Heart Rate, arterial oxygen saturation (SpO2) and quadriceps Root Mean Square (RMS) electromyographical activity) and perceptual responses (overall peripheral discomfort, difficulty breathing and limb discomfort) were recorded. Results: Power output and normalized quadriceps RMS activity were not different between conditions during any exercise bout (p > 0.05) and remained unchanged across time during the constant-effort cycling. SpO2 was lower, while heart rate and ratings of perceived difficulty breathing were higher under HY, compared to NM, at all time points (p < 0.05). During the constant-effort cycling, heart rate, overall perceived discomfort, difficulty breathing and limb discomfort increased with time (all p < 0.05). All variables (except SpO2) increased along with sense of effort during the brief progressive cycling bouts (all p < 0.05). During the two maximal cycling bouts, ratings of overall peripheral discomfort displayed an interaction between time and condition with ratings higher in the second bout under HY vs. NM conditions. Conclusion: During self-selected, constant-effort and brief progressive, sub-maximal, and maximal cycling bouts, mechanical work is regulated in parallel to the sense of effort, independently from peripheral sensations of discomfort.