A better knowledge of the fatigue could be of the greatest importance for the high-grade glioma (HGG) patients, who are a unique and vulnerable population. The aim of this study was to evaluate the occurrence and the predictors of the fatigue in HGG patients, using a specific fatigue scale. The study was designed as a cross-sectional study. The study population included sixty-seven consecutive outpatients with HGG. We used these measures: Brief Fatigue Inventory, Karnofsky Performance Scale, Functional Independence Measure, Brief Psychiatric Rating Scale and Psychological Distress Inventory and SF-36, EORTC QLQ-30 and EORTC QLQ-BN20 for quality of life (QoL). Sixteen out of sixty-seven (23.9 %) patients were affected by Anaplastic Astrocytoma and 51/67 (76.1 %) by Glioblastoma Multiforme. About one-third (36.2 %) of patients had a clinically relevant fatigue (Brief Fatigue Inventory ≥3). In regression analysis, physical and mental aspects of QoL were statistically significant related with fatigue (p < 0.01 and p < 0.02, respectively). Our data underlined the relevant occurrence of fatigue in HGG patients and support the development of further studies exploring a tailored rehabilitation program.