Purpose To compare controlled-release carbamazepine monotherapy (CBZ-CR) with lamotrigine and valproate combination therapy (LTG + VPA) in equivalent total drug load, as initial drug regimen in untreated patients with partial and/or generalized tonic-clonic seizures (GTCS). Methods This unblinded, randomized, 60-week superiority trial recruited patients having two or more unprovoked seizures with at least one seizure during previous three months. After randomization into CBZ-CR or LTG + VPA, patients entered into eight-week titration phase (TP), followed by 52-week maintenance phase (MP). Median doses of CBZ-CR and LTG + VPA were 600 mg/day and 75 mg/day + 500 mg/day, respectively. Primary outcome measure was completion rate (CR), a proportion of patients who have completed the 60-week study as planned. Secondary efficacy measures included seizure-free rate (SFR) for 52-week of MP and time to first seizure (TTFS) during MP. Results Among 207 randomized patients, 202 underwent outcome analysis (104 in CBZ-CR, 98 in LTG + VPA). CR was 62.5% in CBZ-CR and 65.3% in LTG + VPA (p = 0.678). SFR during MP was higher in LTG + VPA (64.1%) than CBZ-CR (47.8%) (P = 0.034). TTFS was shorter with CBZ-CR (p = 0.041). Incidence of adverse effects (AEs) were 57.7% in CBZ-CR and 60.2% in LTG + VPA and premature drug withdrawal rates due to AEs were 12.5% and 7.1%, respectively, which were not significantly different. Conclusion CR was comparable between LTG + VPA and CBZ-CR, however, both SFR for 52-week MP and TTFS during MP were in favor of LTG + VPA than CBZ-CR. The study suggested that LTG + VPA can be an option as initial drug regimen for untreated patients with partial seizures and/or GTCS except for women of reproductive age.