Eccentric contractions induce muscle damage, but less is known about the effects of preceding concentric contractions to eccentric contractions on muscle damage. We compared eccentric-only (ECC) and coupled concentric and eccentric contractions (CON-ECC) of the knee extensors for parameters of neuromuscular fatigue and muscle damage. Methods: Twenty participants (age, 19-36 yr) were randomly placed into an ECC or a CON-ECC group (n = 10 per group), without significant (P > 0.06) differences in baseline neuromuscular variables between groups. The ECC group performed six sets of eight ECC at 80% of ECC one-repetition maximum (1-RMecc), whereas the CON-ECC group performed six sets of eight alternating concentric (CON) and ECC (16 contractions per set) at 80% of CON 1-RM and 1-RMecc, respectively. Maximal voluntary isometric contraction force, rate of force development, resting twitch force, maximal M-wave (M MAX ), voluntary activation, motor evoked potentials, corticospinal silent period, short interval intracortical inhibition, and muscle soreness were measured before, immediately after, and 1-3 d after exercise. Results: No significant (P ≥ 0.09) differences between ECC and CON-ECC were observed for changes in any variables after exercise. However, maximal voluntary isometric contraction force decreased immediately after exercise (ECC: −20.7% ± 12.8%, CON-ECC: −23.6% ± 23.3%) and was still reduced 3 d after exercise (ECC: −13.6% ± 13.4%, CON-ECC: −3.3% ± 21.2%). Rate of force development at 0-30 ms reduced immediately after exercise (ECC: −38.3% ± 33.9%, CON-ECC: −30.7% ± 38.3%). Voluntary activation, resting twitch force, and motor evoked potential/M MAX decreased and corticospinal silent period increased after exercise (all P ≤ 0.03), but short interval intracortical inhibition and M MAX did not change. Muscle soreness developed (P < 0.001) similarly for both groups (peak, 38.5 ± 29.5 mm). Conclusions: CON-ECC did not exacerbate neuromuscular fatigue and muscle damage when compared with ECC, despite twice as many contractions performed. Thus, eccentric contractions (n = 48 in both groups) seemed to mainly mediate the neuromuscular responses observed.