OBJECTIVES: To calculate and compare the incremental cost-utility ratios for standard antiepileptic drug (AED) therapy with and without adjunctive lacosamide in patients with uncontrolled partial-onset seizures. METHODS: The model simulated the treatment pathway of a hypothetical cohort of 1000 patients over two years from the third party payer perspective in the United States in 2010. A decision tree was split into four phases of six months each during which patients can become seizure free, experience a seizure reduction (responder defined as ≥50% reduction in seizures), or withdraw due to non-response. The standard therapy arm included five adjunctive therapies: carbamazepine, lamotrigine, levetiracetam, topiramate, and valproate. The likelihood of being in a particular health state has been estimated from clinical trials data. The cost of general practitioner visits, specialist visits, hospitalizations and emergency department visits were included. Costs and utility values attached to various health states were taken from the published literature. RESULTS: Lacosamide adjunctive therapy was associated with 6,730 avoided seizures and a gain of 38 quality adjusted life-years (QALYs), compared to the standard therapy arm within the two-year timeframe. Treatment with lacosamide was associated with a cost of $223 per seizure avoided, and $39,574 per QALY gained versus standard therapy over two years and falls within acceptable thresholds of cost-effectiveness in the United States. Results calculated for 6-, 12- and 18-month follow-up showed respective incremental cost-utility ratios of $55,465, $46,587 and $44,559 and cost per seizure avoided of $733, $305 and $260. Using a willingness-to-pay threshold of $50,000 per QALY, 77% of the simulations fell below this value after 2 years of treatment.   CONCLUSIONS: Lacosamide was shown to be a cost-effective adjunctive treatment in patients with uncontrolled partial-onset epilepsy in the United States.