This study aimed to investigate mechanisms of neuromuscular fatigue during maximal concentric and isometric leg extensions inducing similar torque decrements. Nine physically active men performed two separate fatiguing sessions maintained until similar torque decreases were obtained. The first session, only conducted under isokinetic concentric conditions (CON), consisted of three series of 30 maximal voluntary concentric knee extensions (60 degrees/s). The second session, exclusively isometric (ISO), mimicked the torque decreases registered during the CON session while performing three long-lasting ISO contractions. Maximal voluntary torque, activation level (twitch interpolation technique), electromyographic activity (root mean square and median frequency) of the vastus lateralis muscle, and electrically evoked doublet-twitch mechanical properties were measured before and at the end of each of the three series. After the three series, similar torque decrements were obtained for both fatiguing procedures. The total fatiguing contraction durations were not different among procedures. With equivalent voluntary torque decrements, the doublet-twitch amplitude reduction was significantly greater (P<0.01) during the two first series of the CON procedure compared with ISO. No difference was observed for the third series. Although no difference was recorded with fatigue for median frequency changes between CON and ISO, activation levels and root mean square values demonstrated greater reductions (P<0.05) for all three series during the ISO procedure compared with CON. Performing CON or ISO fatiguing exercises demonstrated different fatigue origins. With CON exercises, peripheral fatigue developed first, followed by central fatigue, whereas with ISO exercises the fatigue pattern was inverted.