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• The prevalence of IDD in DRE is high. • In DRE, subjects with IDD more likely present depressive or anxious symptoms. • In DRE, subjects with IDD more likely present certain personality disorders. • In DRE, subjects with IDD show lower QOL scores compared to subjects without IDD. • Adequate treatment requires early recognition of IDD and psychiatric comorbidities. This study aims to assess the prevalence of Interictal Dysphoric Disorder (IDD) in drug-resistant epilepsy (DRE) and to describe its clinical and psychopathological profile, including personality, as well as its impact on quality of life (QOL). A retrospective cross-sectional study from an Epilepsy Unit from January 2007 to December 2017. All patients were diagnosed with DRE. Patients underwent a battery of tests (HADS, SCL-90R, PDQ-4+, QOLIE-31) and a psychiatrist assessed the presence of Axis-I disorders and IDD. Statistical procedures were carried out using R-4.0.1 software. A total of 282 patients were included. A statistically significant association was found between IDD and mood and anxiety disorders (p < 0.001 and p < 0.05 respectively), and between IDD and higher scores in all HADS and SCL-90-R items compared to subjects without IDD (p < 0.001). A statistically significant association was also found between IDD and obsessive–compulsive, borderline and depressive personality disorder (p < 0.05). Scores in all QOLIE-31 items except for 'medication effects' were significantly lower in subjects with IDD compared with subjects without IDD (p < 0.001). In DRE, IDD subjects show differences in the psychopathological profile and QOL scores compared to subjects without a diagnosis of IDD. An early diagnosis of IDD could facilitate prompt interventions which might positively impact QOL. [ABSTRACT FROM AUTHOR]