Purpose - To compare the mechanisms of fatigue and recovery between upper and lower limbs in the same subjects. Methods - Twelve healthy young men performed a 2-min sustained maximal voluntary isometric contraction (MVC) of the knee extensors (KE) and on another day a 2-min MVC of the elbow flexors (EF). Neuromuscular function evaluations were performed with both transcranial magnetic and peripheral stimulations before (PRE), at the end of the 2-min MVC, and five more times within 8 min of recovery. Results - Decreases in MVC and cortical voluntary activation were approximately 12% (P < 0.001) and approximately 25% greater (P = 0.04) in KE than EF at end of the 2-min MVC. Conversely, twitch response decreased approximately 29% more (P = 0.02) in EF than KE. Changes in motor-evoked potential with fatigue were not different between upper and lower limbs (P > 0.05), whereas the increase in silent period duration was approximately 30% greater in EF than KE (P < 0.05). Conclusions - Upper and lower limbs presented different magnitudes of total, central and peripheral fatigue. Total neuromuscular fatigue and central fatigue were greater in KE than EF. Conversely, peripheral fatigue and corticospinal inhibition were greater in EF than KE.