Objective: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of syndromes, including Lennox-Gastaut syndrome (LGS), which are refractory to multiple therapies. Perampanel efficacy has been reported in LGS but further real-world evidence is needed in DEEs., Methods: A multicenter, retrospective, 1-year observational study in patients with DEEs on adjuvant perampanel treatment was conducted to assess perampanel safety and effectiveness in this type of patients in a real-world setting. Seizure types [focal onset seizures (FOS), generalized tonic-clonic seizures (GTCS), tonic seizures (TS), atonic seizures (AtS), atypical absences (AA), and myoclonic seizures (MS)] and seizure clusters were divided in different frequency groups: daily, weekly, and monthly seizures, and absent or seizure freedom. Patients could have more than one seizure type. For each frequency group, group change and seizure freedom were analyzed., Results: Eighty-seven patients diagnosed with DEEs (45 males) of median age 22 [1-70] years were included. The most frequent DEEs were LGS (35.6%) and Lennox-like syndrome (37.9%). At baseline 20 patients had three to five types of seizures, 36 patients had two types of seizures and 31 patients had one predominant type of seizure. The mean number of seizure types per patient at baseline was 2.12 ± 0.97 which was reduced to 1.62 ± 0.91 at 12 months (p < 0.001). Overall, 51.7% of patients had a significant improvement in at least one seizure type. At baseline, 45 patients had GTCS, 42 FOS, 41 TS, 18 AA, 16 AtS, 11 MS, and 30 seizures clusters. Seizure freedom for each specific type at 12 months was significantly achieved by 35% of patients with GTCS (p < 0.001), 17% (p = 0.016) with TS and 37% with seizure clusters (p < 0.001). Patients achieved seizure freedom from other seizure types but with no statistical significance: 7% FOS-free, 28% AA-free, 6% Ats-free, and 18% MS-free. Regarding changes of group at 12 months, 22% of TS and 19% of FOS improved significantly to a group with lower seizure frequency (p = 0.004 and p = 0.02, respectively). In remaining groups (4% of GTCS, 11% of AA, 18% of Ats, 18% of MS, and 13% of seizure clusters), the improvement was not statistically significant. Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of efficacy, and 3 (3%) due to seizure worsening. Adverse events, mostly mild or moderate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent., Conclusion: This is the first large-scale real-world study with perampanel across different seizure types in patients with DEEs. Perampanel was effective, especially in GTCS, TS, and FOS, as well as in seizure clusters. Perampanel was generally well-tolerated without unexpected AEs., Competing Interests: Declaration of Competing Interest Pablo Alonso-Singer has received research support from Eisai, and has served as a paid speaker for Eisai, Bial, UCB and Neuraxpharm. Maria José Aguilar has served as a paid speaker for Eisai, Bial, UCB and Neuraxpharm. Javier Oliva has served as a paid speaker for UCB. Andreu Massot-Tarrús has served as a paid speaker and consultant for Bial, Eisai, UCB Pharma and GW pharmaceuticals, and has received research support from Eisai and UCB Pharma. Joaquín Ojeda has served as a paid consultantforEisai and UCB, and has served as a paid speaker for Bial, Eisai, Pfizer, GSK and UCB Pharma, and has received research support from Alter, and travel support from Bial, Kern Pharma, Eisai and UCB. Ángel Aledo-Serranohas received research and educational support from Zogenix, GW, UCB, Bial, Eisai, Sanofi, Neuraxpharm, Arvelle and PTC. Pedro Bermejo has served as a paid speaker for Bial, Eisai, UCB, Cantabria, Kern, Juste, Cardiva2, St. Jude, Abbott, Esteve, Merck, Teva, Novartis, Lilly, Pfizer, Biogen, Ferrer, and Almirall, and as a paid consultant for Ferrer, AB-Biotics, Cardiva2, St. Jude, Abbott, UCB, Eisai, Merck, Sandoz and TFS, and has current collaborating contracts with UCB, MedAvante and Xana Neurodigital Therapies. Maria de Toledo received research and educational support from Eisai, GW, UCB, Bial and Exeltis. Beatriz G. Giráldez received educational support and has served as a paid-consultant for UCB, Bial, Eisai and Neuraxpharm. The remaining authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)