The genesis of dyspnea is complex. It appears to be related to central respiratory drive although prevailing leg fatigue could independently potentiate dyspnea. We hypothesized that experimentally induced leg fatigue generates more intense exertional dyspnea for a given level of ventilatory drive. Following familiarization, 19 healthy subjects (32.2 ± 7.6 yr; 11 men) performed a 5-min treadmill test (speed: ∼4 km/h; grade: ∼25%) on two separate days randomized between control (C) and experimentally induced leg fatigue (E) achieved by repeated knee extension against 40% body weight until task failure. Oxygen uptake (V̇o2, l/min), carbon dioxide output (V̇co2, l/min), ventilation (V̇e, l/min), and respiratory rate (fR) were measured breath by breath. Heart rate (HR) and perceived dyspnea intensity (0–10 numerical scale) were recorded continuously. Data were averaged over 30-s intervals. Exertional dyspnea during E was statistically significantly higher (E vs. C: 4.2 ± 0.2 vs. 3.4 ± 0.2, P < 0.001) and accompanied by a significant increase in V̇e (E vs. C: 61.7 ± 3.7 vs. 55.3 ± 2.8, P = 0.005) and fR (E vs. C: 26.7 ± 1.0 vs. 24.2 ± 1.3, P = 0.036). Dyspnea following E remained significantly higher after allowing for the V̇e confound (ANCOVA, P = 0.003). V̇o2, V̇co2, and HR were not significantly different between two conditions. However, the slopes for dyspnea vs. V̇o2 and dyspnea vs. V̇e were similar between E and C, which suggested that gain in dyspnea per unit change in V̇o2 or V̇e was not altered by leg fatigue. These findings support the hypothesis that the intensity of exertional dyspnea is exacerbated by peripheral afferent information from fatigued leg muscles.