BACKGROUND The subjective feeling of fatigue in myasthenia gravis (MG) is poorly elucidated, in part because it is often confounded with the objective sign of muscle fatigability. Another reason is the paucity of validated fatigue questionnaires in MG. METHODS We applied the 9-item Fatigue Severity Scale (FSS) and the 40-item Fatigue Impact Scale (FIS) to 73 MG patients and 230 age- and sex-matched control subjects. We ascertained levels of education, marital status, and comorbidities such as depression, sleepiness, sleep times and sleep debt. Disease severity was graded according to the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS All fatigue scores, with the exception of the cognitive FIS subscale, were higher in MG patients than controls. In MG, the prevalence of fatigue (defined by FSS scores ≥ 4.0) was 70%. Multiple regression analyses revealed several independent associates of fatigue, including depression (all fatigue scales), MGFA stage (FSS, physical FIS), female sex (cognitive and psychosocial FIS), and sleep debt (physical FIS). CONCLUSION Fatigue in MG is highly prevalent, mainly physical, and influenced by depressive symptoms, disease severity, female sex and sleep debt. Cognitive fatigue in MG may not be a direct disease manifestation, but secondary to depression. The FSS and FIS represent reliable and validated tools, appropriate to discern meaningful clinical aspects of fatigue in MG. Clinical recognition of the complexity of fatigue may foster individualized treatment approaches for affected MG patients.