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Although fatigue is a common non-motor symptom in patients affected by Parkinson's disease (PD), its association with motor and other non-motor symptoms is still largely unclear. We assessed fatigue in PD patients studying the possible association with motor and non-motor symptoms. Eighty-one PD patients were included in the study. The PD Fatigue Scale (PFS) and the Fatigue Severity Scale (FSS) scale were used to measure fatigue. Non-motor symptoms were assessed with the Non-Motor Symptoms Scale (NMSS). Motor impairment was assessed using the modified Hoehn and Yahr (HY) staging and the Unified PD Rating Scale (UPDRS) part-III and IV. Bivariate tests comparing all independent variables between patients with our without fatigue were used. Significant predictors of presence and severity of fatigue were determined with different models of logistic regression analyses. Fatigue severity was significantly higher in female patients. Bivariate test showed significant higher NMSS score in fatigued patients according to PFS (p < 0.00001) and FFS (p < 0.001), while HY was higher only in fatigued patients according to FSS (p < 0.022). Significant correlations between severity of fatigue and HY stage (p < 0.002) and UPDRS-III score (p < 0.001) were found, while, among specific non-motor symptoms, anhedonia presented with the most significant correlation (p < 0.003). Binary logistic regression confirmed NMSS as the main variable predicting presence of fatigue, while HY was significant as predicting variable only in the FSS model. Strongest non-motor symptoms predictors of severity were those included in Domain 3 (mood/anxiety) and Domain 2 (sleep disorders) of the NMSS. A significant increase in severity of fatigue related to the burden of non-motor symptoms (mainly affective and sleep disorders) was observed. Our findings indicate a moderate discrepancy in the ratings of the two fatigue scales, with PFS principally directed towards the burden of non-motor symptoms. Finally, the accurate individuation of the factors underlying fatigue, assessed with the systematic administration of holistic evaluation scales such as the NMSS, might improve current strategies used in the treatment of this disabling condition.