Locomotor muscle fatigue, defined as an exercise-induced reduction in maximal voluntary force, occurs during prolonged exercise but its effects on cardiorespiratory responses and exercise performance are unknown. In this investigation, a significant reduction in locomotor muscle force (-18%, P < 0.05) was isolated from the metabolic stress usually associated with fatiguing exercise using a 100 drop jumps protocol consisting of one jump every 20 s from a 40 cm-high platform. The effect of this treatment on time to exhaustion during high-intensity constant-power cycling was measured in Study 1 (N = 10). In Study 2 (N = 14), test duration (871 ± 280 s) was matched between fatigue and control condition (rest). In Study 1, locomotor muscle fatigue caused a significant curtailment in time to exhaustion (636 ± 278 s) compared to control (750 ± 281 s) (P= 0.003), and increased cardiac output. Breathing frequency was significantly higher in the fatigue condition in both studies despite similar oxygen consumption and blood lactate accumulation. In Study 2, high-intensity cycling did not induce further fatigue to eccentrically-fatigued locomotor muscles. In both studies there was a significant increase in heart rate in the fatigue condition, and perceived exertion was significantly increased in Study 2 compared to control. These results suggest that locomotor muscle fatigue has a significant influence on cardiorespiratory responses and exercise performance during high-intensity cycling independently from metabolic stress. These effects seem to be mediated by the increased central motor command and perception of effort required to exercise with weaker locomotor muscles.