OBJECTIVES: Lennox-Gastaut syndrome (LGS) is a severe form of childhood epilepsy. The cost-effectiveness of rufinamide versus lamotrigine and topiramate as adjunctive therapy in the treatment of LGS from a UK NHS perspective was assessed. METHODS: A semi-Markov model with individual patient simulation was developed to estimate the costs and clinical benefits of the newer antiepileptic drugs over a 3 year time horizon. The outcome measure is the percentage of successfully treated patients, with success defined as £50% reduction in frequency of drop attacks. In the absence of head-to-head clinical trials, indirect comparisons were made among the alternative therapies using placebo as the common comparator. Health states applied in the model were >75% reduction in seizure frequency, 50%-75% reduction, <50% reduction and death. Transition probabilities were derived from patient level trial data on rufinamide and published clinical trials for the comparators. Estimates for resource use were derived from interviews with 5 practicing paediatric epileptologists, to which published UK unit costs were applied. Results of 10,000 Monte Carlo simulations were bootstrapped to conduct probabilistic sensitivity analysis. RESULTS: Over 3 years 11.3% of rufinamide patients were treated successfully compared to 7.2% and 5.2% with topiramate and lamotrigine respectively. Total discounted costs of treatments were respectively £50,985, £50,730 and £50,975 with a highly right-skewed distribution. Mean incremental cost-effectiveness ratios (ICER) for rufinamide were £6,215 (90%CI: dominant–£40,000) and £172 (dominant – £19,100) per 1% increase in success rate versus topiramate and lamotrigine respectively. At £13,000 per 1% increase in successfully treated patients over 3 years rufinamide is has the highest probability of being cost-effective. Shorter time horizons and higher hospitalisation rates improved the cost-effectiveness of rufinamide. CONCLUSION: Rufinamide is a cost-effective therapy compared to topiramate and lamotrigine as adjunctive therapy in achieving greater than 50% reduction in frequency of drop attacks in LGS.