Objective: To determine whether patients who fail their first antiepileptic drug (AED) have better neuropsychiatric and quality-of-life (QOL) outcomes if substituted to levetiracetam monotherapy compared with a second older AED. Design: Randomized comparative trial. Participants with partial epilepsy who had failed monotherapy with phenytoin sodium, carbamazepine, or valproate sodium were randomized to substitution monotherapy with levetiracetam or a different older AED. Assessments were performed at baseline, 3 months, and 12 months using questionnaires measuring neuropsychiatric, QOL, seizure control,AED adverse effects, and neurocognitive outcomes. Setting: Epilepsy service of a teaching hospital. Patients: Fifty-one patients were randomized to levetiracetam and 48 were randomized to a second older AED (25 to valproate and 23 to carbamazepine). Main Outcome Measures: Proportions showing improvements in depression (on the Hospital Anxiety and Depression Scale) and QOL scores (on the 89-item Quality of Life in Epilepsy Inventory) at 3 months. Results: There were no differences between the groups in depression scores at 3 months (improvement in 17 of 43 patients [39.5%] in the levetiracetam group and 15 of 44 patients [34.1%] in the older AED group; P =.60), but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory compared with the levetiracetam group (27 of 38 patients [71.1%] vs 21 of 43 patients [48.8%], respectively; P =.04). The QOL, anxiety, and AED adverse effects scores were improved in both groups at 3 and 12 months after randomization. Conclusions: Substitution monotherapy in a patient experiencing ongoing seizures or tolerability issues is associated with sustained improvements in measures of QOL, psychiatric, and adverse events outcomes. Patients switched to levetiracetam do not have better outcomes than those switched to a second older AED. Trial Registration: anzctr.org.au Identifier: ACTRN12606000102572.