Purpose: Given the increased level of fatigue frequently reported by patients with Parkinson's disease (PD), this study investigated the interaction between central and peripheral components of neuromuscular fatigue (NF) in this population compared with healthy peers. Methods: Changes in maximal voluntary activation (ΔVA, central fatigue) and potentiated twitch force (ΔQ tw,pot , peripheral fatigue) pre-post exercise were determined via the interpolated twitch technique in 10 patients with PD and 10 healthy controls (CTRL) matched for age, sex, and physical activity. Pulmonary gas exchange, femoral blood flow, and quadriceps EMG were measured during a fatiguing exercise (85% of peak power output [PPO]). For a specific comparison, on another day, CTRL repeat the fatiguing test matching the time to failure (TTF) and PPO of PD. Results: At 85% of PPO (PD, 21 ± 7 W; CTRL, 37 ± 22 W), both groups have similar TTF (~5.9 min), pulmonary gas exchange, femoral blood flow, and EMG. After this exercise, the maximal voluntary contraction (MVC) force and Q twpot decreased equally in both groups (−16%, P = 0.483; −43%, P = 0.932), whereas VA decreased in PD compared with CTRL (−3.8% vs −1.1%, P = 0.040). At the same PPO and TTF of PD (21 W; 5.4 min), CTRL showed a constant drop in MVC, and Q twpot (−14%, P = 0.854; −39%, P = 0.540), instead VA decreased more in PD than in CTRL (−3.8% vs −0.7%, P = 0.028). Conclusions: In PD, central NF seems exacerbated by the fatiguing task which, however, does not alter peripheral fatigue. This, besides the TTF like CTRL, suggests that physical activity may limit NF and counterbalance PD-induced degeneration through peripheral adaptations. Key Words: MUSCLE DYSFUNCTION, NEUROMUSCULAR FATIGUE, PARKINSON'S DISEASE P arkinson's disease (PD) is a neurological disease with an increasing prevalence, affecting 1% of people older than 60 yr and 3% older than 80 yr worldwide (1). Motor symptoms, including bradykinesia, rigidity, resting tremor, and postural impairment are the cardinal features of PD (2). However, numerous nonmotor symptoms have been increasingly recognized as part of the clinical spectrum of PD and often can dominate the clinical presentation (2) Specifically, fatigue, defined as a subjective feeling of exhaustion, weariness, or increased sense of effort disproportioned to the actual performance, seems to be more pronounced in patients with PD and affects indeed almost 50% of patients (3,4). Arguably, neuromuscular fatigue (NF) is defined as the gradual reduction in the ability to exert muscle force or power during exercise and has central and peripheral components (5). Central fatigue describes the impairment of the neural drive to a muscle, whereas peripheral fatigue entails biochemical changes occurring at or distally to the neuromuscular junction (6). So far, the symptom of fatigue in PD has been evaluated through questionnaires or self-report (7), and only few studies have examined the neurophysiological components of NF with accurate methods in patients with PD (8) and, even le...