Greater peripheral quadriceps fatigue at the voluntary termination of single-leg knee-extensor exercise (KE), in comparison to whole-body cycling, has been attributed to confining group III and IV skeletal muscle afferent feedback to a small muscle mass, enabling the central nervous system (CNS) to tolerate greater peripheral fatigue. However, as task specificity and vastly differing systemic challenges may have complicated this interpretation, 8 males were studied during constant workload trials to exhaustion at 85% of peak workload during single- and double-leg KE. It was hypothesized that due to the smaller muscle mass engaged during single-leg KE, a greater magnitude of peripheral quadriceps fatigue would be present at exhaustion. Vastus lateralis integrated electromyogram (iEMG) signal relative to the first minute of exercise, pre- to post-exercise maximal voluntary contractions (MVCs) of the quadriceps, and twitch-force evoked by supramaximal magnetic femoral nerve stimulation (Q_tw,pot) quantified peripheral quadriceps fatigue. Trials performed with single-leg KE (8.1±1.2 min; 45±4 W) resulted in significantly greater peripheral quadriceps fatigue than double-leg KE (10±1.3 min; 83±7 W), as documented by changes in the iEMG signal (147±24 vs. 85±13%), MVC (-25±3 vs. -12±3%), and Q_tw,pot (-44±6 vs. -33±7%), for single- and double-leg KE, respectively. Therefore, avoiding concerns over task specificity and cardiorespiratory limitations, this study reveals that a reduction in muscle mass permits the development of greater peripheral muscle fatigue and supports the concept that the CNS tolerates a greater magnitude of peripheral fatigue when the source of group III/IV afferent feedback is limited to a small muscle mass.