OBJECTIVE: This study assesses the efficacy, safety, and tolerability of cenobamate using long-term real-world data, incorporating both seizure reduction and seizure-freedom periods, and examines baseline clinical variables to determine predictors of response. METHODS: We retrospectively analyzed all patients prescribed cenobamate from May 2020 to July 2021. The primary outcome was 12-month seizure frequency reduction for each seizure type, stratified by baseline seizure frequency (higher vs lower frequency: ≥2 seizures vs <
2 seizures in the preceding 3 months). Logistic regression identified seizure response predictors. We assessed longest seizure-free periods, considering seizure type and baseline frequency, further differentiating the higher-frequency group into weekly and monthly subgroups. We examined retention, safety, and tolerability. RESULTS: Of 182 patients taking cenobamate, 170 had focal epilepsy. Among those 170, the 12-month retention rate was 82.4%, decreasing to 75% at last follow-up. In patients with higher-frequency baseline seizures, ≥50% seizure reduction rates were 47% (95% confidence interval [CI] = 38%-57%) for focal impaired awareness seizures (FIAS) and 58% (95% CI = 43%-71%) for focal to bilateral tonic-clonic seizures (FBTCS). In patients with lower-frequency seizures, rates were 53% for FIAS (95% CI = 31%-74%) and 68% (95% CI = 49%-82%) for FBTCS. Factors linked to 100% seizure reduction were lower baseline seizure frequency, fewer failed medications, and concomitant clobazam use. Most patients achieving seizure freedom did so at 200 mg/day, although higher doses also showed efficacy, particularly for FBTCS. Among patients with seizures affecting awareness, 7%-43% had ≥12 months of freedom from such seizures. Among patients with FBTCS, 17%-56% had ≥12 months of freedom from FBTCS. Patients with higher-frequency baseline seizures had lower rates of seizure freedom. Adverse effects were reported by 52%, with drowsiness being most common (32%). One patient developed depression necessitating hospitalization. SIGNIFICANCE: Cenobamate is an efficacious drug. Baseline clinical features of seizure type, lower frequency, fewer failed medications, and clobazam use are associated with treatment response and can inform decisions of trialing cenobamate before considering epilepsy surgery.