Background: Perampanel (PER) is an antagonist of AMPA receptors that has been approved for adjunctive treatment of partial-onset seizures. Aims: To evaluate effectiveness and safety of PER as add-on treatment in patients with severely refractory focal epilepsy. Methods: PER was introduced as add-on treatment in 22 consecutive patients with drug-resistant focal epilepsy. PER was started with 2 mg/day at bedtime and was up-titrated by 2 mg/day every 2–4 weeks. Results: All patients suffered from severely refractory focal epilepsy (86% took 2 or more AEDs prior PER initiation; 40% had been submitted to surgery or were surgery candidates; 7 had VNS). After 12 months since PER initiation, the retention rate was 54.5% and the responder rate was 27.2%, including 9.1% seizure-free patients. Mean PER dose in the responders was 8 mg/day (range 4–10). Most common side effects were tiredness, behavioral changes (primarily aggressivity), dizziness and were reported in 59.1% of patients, leading to PER discontinuation in 31.8% of subjects. Conclusions: PER as add-on treatment can achieve clinically meaningful improvement in patients suffering from severely refractory focal epilepses. Further studies are warranted to explore the tolerability profile, with particular focus on psychiatric adverse events.