PURPOSE: To evaluate the efficacy of cenobamate (CNB) in adults with focal epilepsy based on the number of previous lifetime antiseizure medications (ASMs). METHODS: Twenty patients receiving add-on treatment with CNB with <
6 lifetime ASMs were retrospectively compared to 20 Patients with >
10 ASMs and approximately the same age. Efficacy was assessed at 3, 6, and 12 months following CNB initiation. RESULTS: In patients with <
6 lifetime ASMs, seizure frequency significantly decreased at 3, 6, and 12 months (p = 0.03, 0.027, 0.048, respectively), while no significant changes were observed in the >
10 lifetime ASM group. The median percentage of seizure reduction in the <
6 lifetime ASMs group was 58 % at 3 months, 50 % at 6 months, and 92 % at 12 months, compared to 36 %, 50 %, and 42 % in the >
10 lifetime ASM group. The seizure-free rate was significantly higher in the <
6 lifetime ASMs group at all-time points (p <
0.01), despite a lower median daily dose of CNB in this group. There was a trend toward higher responder rates at 12 months in the <
6 lifetime ASMs group, again despite the lower median daily dose of CNB. CONCLUSIONS: This study highlights greater efficacy of CNB in patients with <
6 lifetime ASMs, showing a significantly higher seizure-free rate and greater seizure reduction compared to those with >
10 lifetime ASMs. Despite lower overall response in the latter group, CNB treatment still provided meaningful benefits in highly drug-resistant epilepsy.