OBJECTIVES: Effective seizure control is integral to treatment of Lennox-Gastaut syndrome (LGS), a debilitating form of epilepsy characterized by developmental disorders and frequent drop attacks. In an indirect comparison of antiepileptic drugs (AEDs) FDA-approved for LGS, clobazam was associated with the greatest effect size for decreasing drop attacks. We developed an economic model to evaluate outcomes and costs of clobazam, from a payer perspective, vs. lamotrigine, rufinamide, and topiramate as adjunctive therapy for LGS. METHODS: Baseline seizure frequency (132/month) and AED efficacy were modeled through clinical trial data. Costs of treating drop seizures were derived from a study of administrative claims data from a large US managed health care plan affiliated with OptumInsight, with the assumption that 2.3% of drop seizures led to medical care. Seizure frequency and percentage of patients free of drop seizures were evaluated over a 3-month horizon. Clobazam and rufinamide were also evaluated over 2 years (assumption: 128 seizures/month at baseline). Sensitivity analyses were performed. RESULTS: Results suggest that LGS patients receiving clobazam had 226 drop seizures over 3 months, compared with 261, 275, and 281 for rufinamide, topiramate, and lamotrigine, respectively. More than 21% of patients receiving clobazam were free of drop seizures after 3 months, vs. <5% in each comparator group. Drug and medical costs for patients receiving clobazam totaled $29,000, vs. $32,000–33,000 for comparators. Clobazam was also more efficacious and less costly than rufinamide over a 2-year horizon. Alternative analyses with assumptions of lower rates of seizures upon discontinuation did not alter conclusions. Assumption that fewer drop seizures require medical care (0.5% vs. 2.3%) reduced the short-term but not the long-term cost effectiveness of clobazam. CONCLUSIONS: Medically attended drop seizures are a major cost driver in LGS. For these LGS patients, clobazam may be cost-saving.