PURPOSE: The present study evaluated whether patients with epilepsy who received both levetiracetam (LEV) and perampanel (PER) therapy showed side effects of irritability. The study also examined the relationship between patient characteristics and irritability when it occurred as a side effect. METHODS: We retrospectively examined medical records of 98 patients with epilepsy who were treated with both LEV and PER at the Department of Psychiatry in the Epilepsy Center of Nishiniigata Chuo National Hospital in Japan. We performed multiple regression analyses with the presence/absence of irritability due to LEV or PER as the dependent variables and clinical characteristics of the patients as independent variables. RESULTS: LEV and PER caused irritability in 7 and 17 of 98 patients, respectively. LEV- and PER-related irritability did not occur in the same patients. A logistic multiple regression analysis revealed that EEG findings of temporal focal epileptic discharge were significantly associated with increased incidence of irritability due to LEV. LEV-related irritability decreased significantly with higher dosages of LEV. Another logistic multiple regression analysis revealed that a psychiatric comorbidity of irritability and EEG findings of nontemporal focal epileptic discharge were significantly associated with increased incidence of irritability due to PER. CONCLUSIONS: LEV and PER cause irritability in different patient groups. Additionally, irritability as a side effect was present only at low dosages of LEV, but PER tended to cause irritability even at high dosages.