Neuromuscular (NM), cardiorespiratory, and perceptual responses to maximal-graded exercise using different amounts of active muscle mass remain unclear. We hypothesized that during dynamic exercise, peripheral NM fatigue (declined twitch force) and muscle pain would be greater using smaller muscle mass, whereas central fatigue (declined voluntary activation) and ventilatory variables would be greater using larger muscle mass. Twelve males (29.8 ± 4.7 years) performed two ramp-incremental cycling tests until task failure: 1) single-leg (SL) with 10 W·min-1 ramp and 2) double-leg (DL) with 20 W·min-1 ramp. NM fatigue was assessed at baseline, task failure (post), and after 1, 4, and 8 min of recovery. Cardiorespiratory and perceptual variables [i.e., ratings of perceived exertion (RPE), pain, and dyspnea] were measured throughout cycling. Exercise duration was similar between sessions (SL: 857.7 ± 263.6 s; DL: 855.0 ± 218.8 s; P = 0.923), and higher absolute peak power output was attained in DL (SL: 163.2 ± 43.8 W; DL: 307.0 ± 72.0 W; P < 0.001). Although central fatigue did not differ between conditions (SL: -6.6 ± 6.5%; DL: -3.5 ± 4.8%; P = 0.091), maximal voluntary contraction (SL: -41.6 ± 10.9%; DL: -33.7 ± 8.5%; P = 0.032) and single twitch forces (SL: -59.4 ± 18.8%; DL: -46.2 ± 16.2%; P = 0.003) declined more following SL. DL elicited higher peak oxygen uptake (SL: 42.1 ± 10.0 mL·kg-1·min-1; DL: 50.3 ± 9.3 mL·kg-1·min-1; P < 0.001), ventilation (SL: 137.1 ± 38.1 L·min-1; DL: 171.5 ± 33.2 L·min-1; P < 0.001), and heart rate (SL: 167 ± 21 bpm; DL: 187 ± 8 bpm; P = 0.005). Dyspnea (P = 0.025) was higher in DL; however, RPE (P = 0.005) and pain (P < 0.001) were higher in SL. These results suggest that interplay between NM, cardiorespiratory, and perceptual determinants of exercise performance during ramp-incremental cycling to task failure is muscle mass dependent.