ABSTRACTObjectiveFatigue is a significant symptom in patients with spinocerebellar ataxia type 3 (SCA3). This study explores the role of fatigue in SCA3, examining its impact on quality of life and its potential as an indicator of disease progression.MethodsWe prospectively recruited 128 molecularly confirmed SCA3 patients and 125 sex‐, age‐, and education‐matched healthy controls (HCs). Age at onset, disease duration, length of normal and expanded CAG repeats, and 14‐item Fatigue Scale score were compared. MRIs evaluated the cerebellum and brain lesions.ResultsOur study found that the preataxic SCA3 group exhibited lower fatigue incidence and score than HCs (Incidence: 13% vs. 36%, p = 0.031; FS‐14 score: 3.0 ± 2.7 vs. 5.6 ± 2.8, p < 0.001). Ataxic SCA3 patients experienced significantly higher fatigue incidence and score compared to both the preataxic SCA3 group (Incidence: 63.8% vs. 13%, p < 0.001; FS‐14 score: 8.1 ± 3.9 vs. 3.0 ± 2.7, p < 0.001) and HCs (Incidence: 63.8% vs. 36%, p < 0.001; FS‐14 score: 8.1 ± 3.9 vs. 5.6 ± 2.8, p < 0.001). Moreover, fatigue severity in SCA3 correlated with disease duration and expanded CAG repeat length. Neuroanatomical correlations revealed volume reductions in cortical and cerebellar regions linked to higher physical and mental fatigue scores in SCA3 patients.ConclusionsMonitoring fatigue effectively evaluates a patient's overall quality of life and disease progression, making it a key indicator. Future treatments can target specific brain regions, with their effectiveness being evaluated through FS‐14 assessments of fatigue changes.