We aimed to assess the relapse rate of epilepsy, prospectively attributable to antiepileptic drug (AED) withdrawal in seizure-free patients and to determine the risk factors for seizure recurrence. Seventy-nine patients with epilepsy who were seizure-free for at least 4 years were enrolled into the study. The AEDs were tapered by one-sixth every 2 months. The EEG and clinical examination were performed at the beginning; at each visit during discontinuation and 2, 6, 12, 24, and 36 months after the complete drug withdrawal. For each patient, records were obtained of the main demographic and clinical variables. A total of 49 patients completed the discontinuation programme. Twenty-eight patients (57%) relapsed while 21 of those (42.8%) did not suffer a relapse at the end of the study period. In patients discontinuing treatment, the probability of relapse was 21.4% during the tapering period (especially in the last months), 28.6% at 1 month, 14.3% at 3 months, 3.6% at 6 months, 7.1% at 12 months, 17.8% at 24 months, and 7.1% at 36 months. The age at onset of epilepsy and the duration of active disease were found to affect the risk of relapse. Although drug withdrawal could be considered in adult patients free of seizures for 4 years, the final decision should be tailored to the patient's clinical, emotional, and socio-cultural profile.