Optimal antiepileptic drug treatment in patients with learning disability (LD) represents a particular challenge. These patients are often unable to report toxicity, and side effects may manifest as behavioral problems. The aim of this open study was to compare efficacy and tolerability of levetiracetam (LEV) in patients with LD and those without LD. One hundred eighty-four consecutive adult patients who received LEV were followed for an average of 8.1 months. Fifty-six patients (30%) had LD. Thirty-nine percent of patients with refractory epilepsy (37% with and 40% without LD) had > 50% seizure reduction. Significantly more behavioral side effects (23% vs 10%) and a tendency toward less reported somatic central nervous side effects were found in the LD group. We conclude that LEV is equally effective and well tolerated in both patients with LD and patients without LD. However, behavioral problems are more frequent in patients with LD, whereas the tendency toward seizure increase is not enhanced.