We asked whether the central effects of fatiguing locomotor muscle fatigue exert an inhibitory influence on central motor drive to regulate the total degree of peripheral fatigue development. Eight cyclists performed constant-workload prefatigue trials (a) to exhaustion (83% of peak power output (Wpeak), 10 ± 1 min; PFT83%), and (b) for an identical duration but at 67%Wpeak (PFT67%). Exercise-induced peripheral quadriceps fatigue was assessed via changes in potentiated quadriceps twitch force (ΔQtw,pot) from pre- to post-exercise in response to supra-maximal femoral nerve stimulation (ΔQtw,pot). On different days, each subject randomly performed three 5 km time trials (TTs). First, subjects repeated PFT83% and the TT was started 4 min later with a known level of pre-existing locomotor muscle fatigue (ΔQtw,pot−36%) (PFT83%-TT). Second, subjects repeated PFT67% and the TT was started 4 min later with a known level of pre-existing locomotor muscle fatigue (ΔQtw,pot−20%) (PFT67%-TT). Finally, a control TT was performed without any pre-existing level of fatigue. Central neural drive during the three TTs was estimated via quadriceps EMG. Increases in pre-existing locomotor muscle fatigue from control TT to PFT83%-TT resulted in significant dose-dependent changes in central motor drive (−23%), power output (−14%), and performance time (+6%) during the TTs. However, the magnitude of locomotor muscle fatigue following various TTs was not different (ΔQtw,pot of −35 to −37%, P= 0.35). We suggest that feedback from fatiguing muscle plays an important role in the determination of central motor drive and force output, so that the development of peripheral muscle fatigue is confined to a certain level.