PURPOSE: Fatigue represents a frequent complaint in epileptic patients (EP). This study attempted to evaluate fatigue in both conditions (inter-ictally and post-ictally) and to investigate the relative contribution of depression, sleepiness and epilepsy characteristics. METHODS: Consecutive EP were enrolled prospectively during a 3-month period, providing they were aged over 15 and able to fill auto-questionnaires. Age, gender, co-morbidities, seizure frequency, treatment, epilepsy syndrome, seizure lateralization and localization and last seizure occurrence were collected. Fatigue, depression and sleepiness were evaluated in both groups using the Fatigue Impact Scale (FIS), the Beck Depression Inventory (BDI), and the Epworth Sleepiness Scale (ESS). Furthermore, FIS was prospectively scored by patients post-ictally (within 24h after an incident seizure). RESULTS: 122 EP filled inclusion criteria (65 women, mean age 39±15). Among them, 82% presented with non-idiopathic partial epilepsy and 18% idiopathic generalized epilepsy. EP exhibit high chronic fatigue scores (62/160) irrespective of the type of epilepsy, seizure frequency, and number of antiepileptic drugs. FIS score was higher in post-ictally (79/160) than inter-ictally. FIS positively correlated with BDI and ESS. DISCUSSION: Chronic inter-ictal and post-ictal fatigue could represent a further complication of epilepsy, associated with depression. The impact of fatigue should be considered with the aim of improving quality of life and care of patients with epilepsy.