The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg twice daily, as add-on treatment without titration in patients with refractory epilepsy. After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week double-blind period, then levetiracetam 4000 mg daily in a 24-week open-label phase. Somnolence was the most common reason for discontinuation, and along with asthenia, occurred more frequently with levetiracetam than placebo. Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily (48.1% [P < 0.05] and 28.6% [NS], respectively) than placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with patients initiated on levetiracetam 2000 mg daily. Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy in patients with partial and/or generalized seizures. The higher dose may be related to an increased incidence of somnolence and is not necessarily more effective than the lower dose.