This open-label, multicenter, randomized phase IV trial (NCT01498822) of noninferiority design compared the long-term effectiveness, safety, and tolerability of levetiracetam (LEV) monotherapy with those of oxcarbazepine (OXC) monotherapy in adults with newly diagnosed focal epilepsy. Korean patients (16–80 years), with ≥2 unprovoked focal seizures in the year preceding the trial, who had not taken any antiepileptic drugs (AEDs) in the last 6 months, were randomized to receive LEV or OXC (1:1). Effectiveness, safety, and tolerability were assessed over a 50-week period. Treatment failure rates (per protocol set) were 15/118 (12.7%) in the LEV-treated group and 30/128 (23.4%) in the OXC-treated group, an absolute difference of −10.7% (95% confidence interval [CI] −20.2, −1.2). Because the upper 95% CI limit was less than the pre-specified noninferiority margin of 15%, LEV was considered noninferior to OXC. Twenty-four-week and 48-week seizure freedom rates were 53.8% and 34.7% for LEV vs. 58.5% and 40.9% for OXC. Both LEV and OXC were well tolerated, with 8.7% and 8.6% of patients reporting serious treatment-emergent adverse events, respectively. By comparing LEV with OXC, another newer AED, LEV can be considered a useful option as initial monotherapy for patients with newly diagnosed focal epilepsy.