The aim of this document is to provide evidence-based recommendations for the medical treatment of depression in adults with epilepsy. The working group consisted of members of an ad hoc Task Force of the International League Against Epilepsy (ILAE) Commission on Psychiatry, ILAE Executive and the International Bureau for Epilepsy (IBE) representatives. The development of these recommendations is based on a systematic review of studies on the treatment of depression in adults with epilepsy, and a formal adaptation process of existing guidelines and recommendations of treatment of depression outside epilepsy using the ADAPTE process. The systematic review identified 11 studies on drug treatments (788 participants, class of evidence III and IV); 13 studies on psychological treatments (998 participants, class of evidence II, III and IV); and 2 studies comparing sertraline with cognitive behavioral therapy (CBT; 155 participants, class of evidence I and IV). The ADAPTE process identified the World Federation of Societies of Biological Psychiatry guidelines for the biological treatment of unipolar depression as the starting point for the adaptation process. This document focuses on first-line drug treatment, inadequate response to first-line antidepressant treatment, and duration of such treatment and augmentation strategies within the broader context of electroconvulsive therapy, psychological, and other treatments. For mild depressive episodes, psychological interventions are first-line treatments, and where medication is used, selective serotonin reuptake inhibitors (SSRIs) are first-choice medications (Level B). SSRIs remain the first-choice medications (Level B) for moderate to severe depressive episodes; however, in patients who are partially or non-responding to first-line treatment, switching to venlafaxine appears legitimate (Level C). Antidepressant treatment should be maintained for at least 6 months following remission from a first depressive episode but it should be prolonged to 9 months in patients with a history of previous episodes and should continue even longer in severe depression or in cases of residual symptomatology until such symptoms have subsided.