Objective. This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Methods. This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician’s choice). Patients were converted during an ⩽8-week Escalation/Taper Phase from their prestudy antiepileptic drug (carbamazepine, phenytoin, or valproate) to lamotrigine via a protocol-specified dosing algorithm or to conventional therapy via standard dosing guidelines. After monotherapy was achieved, patients continued in the study for a 24-week Maintenance Phase. Results. More lamotrigine patients (65%) than conventional therapy patients (57%) completed the 24-week Maintenance Phase (primary efficacy endpoint). The mean time to withdrawal from the study was 175 days (SD=83.1) for lamotrigine patients compared with 156 days (SD=80.7) for conventional therapy patients. Adverse events, the most common reason for discontinuing the Maintenance Phase, accounted for 16% of withdrawals among lamotrigine patients compared with 26% of withdrawals among conventional therapy patients. The mean reduction in seizure frequency was 53% (SD=55.1) for patients using lamotrigine compared with 32% (SD=149.9) for patients using conventional therapy. Humanistic measures including investigator global assessment, the patient self-assessment, and QOLIE-31 scores show that lamotrigine monotherapy was perceived by both physicians and patients to have benefits over monotherapy with conventional antiepileptic drugs. Conclusions. Converting from monotherapy with a less effective or poorly tolerated conventional antiepileptic drug to monotherapy with lamotrigine is associated with better clinical and humanistic outcomes than converting to an alternative conventional antiepileptic drug.