PURPOSE: To evaluate the efficacy and tolerability of adjunctive levetiracetam in very young children (aged 1 month to <4 years) with partial-onset seizures inadequately controlled with one or two antiepileptic drugs. METHODS: This multicenter, double-blind, randomized, placebo-controlled study consisted of a 48-h inpatient baseline video-EEG (electroencephalography) and a 5-day inpatient treatment period (1-day up-titration; 48-h evaluation video-EEG in the last 2 days). Children who experienced at least two partial-onset seizures during the 48-h baseline video-EEG were randomized to either levetiracetam [40 mg/kg/day (age 1 to <6 months); 50 mg/kg/day (age >or=6 months to <4 years] or placebo. RESULTS: Of 175 patients screened, 116 patients were randomized [60 levetiracetam; 56 placebo; intent-to-treat (ITT) population], and 111 completed the study. The responder rate in average daily partial-onset seizures frequency (48-h video-EEG monitoring; primary efficacy variable) was 43.1% for levetiracetam [modified ITT (mITT) = 58] versus 19.6% for placebo (mITT = 51; p=0.013), with odds ratio for response 3.11 [95% confidence interval (CI), 1.22-8.26]. The median percent reduction from baseline in average daily partial-onset seizure frequency was 43.6% for levetiracetam and 7.1% for placebo with a median difference between treatment groups of 39.2% (95% CI, 17.5-62.2; p < 0.001). In general, levetiracetam was well tolerated. Treatment-emergent adverse events were reported by 55.0% levetiracetam- and 44.6% placebo-treated patients (ITT population). The most frequently reported adverse events were somnolence (13.3% levetiracetam, 1.8% placebo) and irritability (11.7% levetiracetam, 0% placebo). DISCUSSION: Adjunctive levetiracetam is an efficacious and well-tolerated treatment for partial-onset seizures in infants and young children.