Objective: In a nation-wide population-based longitudinal register linkage study to investigate long-term response to antidepressants in patients with depression with and without comorbid epilepsy. Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 1487 patients with depression and comorbid epilepsy and 71,163 patients with depression without comorbid epilepsy during a study period from 1995 to 2017. Response was defined as continuous monotherapy with an antidepressant drug without switch to or add-on of another antidepressant drug, an antipsychotic drug or lithium or hospitalization during an up to ten-year follow-up period. We calculated standardized absolute risks and differences thereof with respect to age, gender, socioeconomic status and comorbidity with other physical disorders than epilepsy. Results: In patients with depression, response to antidepressants was decreased with versus without comorbid epilepsy during the ten-year follow-up period. One year after start of antidepressant treatment the proportion of responders was 12% (CI: 10%-14%) lower in patients with versus without comorbid epilepsy in the standardized population. Response to antidepressants were specifically decreased among younger and unemployed patients with depression and comorbid epilepsy. Limitations: We did not include sub-analyses according to subtypes of epilepsy. Conclusions: Response to antidepressants was decreased in patients with comorbid epilepsy versus without comorbid epilepsy at all time points during a ten-year follow-up period. The study highlights the need for closely clinical monitoring and psychological support for patients with depression and comorbid epilepsy and emphasize the need for further long-term studies of effect of interventions.