The long-term outcome with respect to seizure relapse after planned discontinuation of antiepileptic drugs (AEDs) in seizure-free patients is not well known. Relapse and its treatment outcome were evaluated in a longitudinal population-based study of 148 patients from the onset of their epilepsy to an average follow-up of 37 years. During the study, AEDs were completely discontinued by 90 patients; 58 patients remained on medication. Seizure relapse after AED discontinuation was observed in 33 (37%) of 90 patients at an average follow-up of 32 years. Among 8 of the 33 patients who elected to restart AEDs, 2 achieved 5-year terminal remission (5YTR), but only 10-19 years after restarting treatment. The other 6 patients never achieved 5YTR, and 2 of the 6 never entered a 5-year remission period during follow-up. Factors associated with failure to reach 5YTR after treatment of relapse were symptomatic etiology and localization-related epilepsy. In conclusion, drug discontinuation after seizure freedom results in relapse in one-third of patients. Reinstitution of a medication that worked for years fails to achieve control in one of four patients. These risks need to be considered, although there is no evidence that discontinuation is responsible for the poor prognosis for treatment of seizure recurrence.