This prospective uncontrolled open study explored the efficacy and long-term tolerability of sulthiame (STM) in 52 patients with refractory epilepsy and learning disability. Thirty-six patients completed a 14-weeks trial period with STM and 22 patients achieved a seizure reduction>50% of which three became seizure-free. Twenty-six patients continued taking STM for now up to 120 weeks, one continued to be seizure-free, whilst five patients stopped STM during this period. These promising observations require further evaluation in a controlled trial.