Purpose: In this prospective study, we compared the long-term cognitive and behavioral effects of lamotrigine (LTG) and carbamazepine (CBZ) in patients with newly diagnosed or untreated partial epilepsy. Methods: This was a multicenter, open-label, randomized study that compared monotherapy with LTG and CBZ in newly diagnosed or untreated patients with partial epilepsy. We employed an 8-week titration period and a 40-week maintenance period. Neuropsychological tests, Symptom Check List-90, and QOLIE-31 were assessed at baseline, 16 weeks, and 48 weeks after drug treatment. A group-by-time interaction was the primary outcome measure and was analyzed by use of the linear mixed model. Results: A total of 110 patients were eligible and 73 completed the 48-week study (LTG, n = 39; CBZ, n = 34). Among the cognitive tests, significant group-by-time interaction was identified only in phonemic fluency of Controlled Oral Word Association Task (p = 0.0032) and Stroop Color-Word Interference (p = 0.0283), with a significant better performance for LTG group. All other neuropsychological tests included did not show significant group-by-time interactions. Among the subscales of Symptom Check List-90, significant group-by-time interactions were identified in Obsessive-Compulsive (p = 0.0005), Paranoid Ideation (p = 0.0454), Global Severity Index (p = 0.0194), and Positive Symptom Total (p = 0.0197), with a significant improvement for CBZ group. QOLIE-31 did not show significant group-by-time interactions. Conclusion: Our data suggest that epilepsy patients on LTG have better performance on phonemic fluency and the task of Stroop Color-Word Interference than do patients on CBZ, whereas patients on CBZ had more favorable behavioral effects on two subscales and two global scores of Symptom Check List-90 than did patients on LTG.