Lamotrigine (LTG) was added to other antiepileptic drugs (AEDs) in a study of adjunctive therapy. In addition to seizure control and adverse effects, patients were evaluated for changes in mood states and quality of life. The Profile of Mood States (POMS) and 31-item Quality of Life in Epilepsy (QOLIE-31) instruments were administered at baseline (N=196), after addition of LTG as adjunctive treatment (N=155), and after withdrawal of other drugs to LTG monotherapy (N=51). POMS scores correlated highly with the QOLIE-31 Emotional Well-Being subscale, a known measure of mood. All POMS subscales were significantly improved (all P<0.0001) at the end of the adjunctive therapy phase. POMS scores remained significantly better than baseline among patients completing the conversion to monotherapy (all P<0.003). Minimal clinically important changes were determined for POMS scores. These data indicate that LTG improves mood states to a clinically important degree, even in the presence of other AEDs. The improvement likely was not a synergy but attributable only to LTG because it remained stable after withdrawal of the other AEDs.