© 2021 Elsevier Inc.Objective: It is remarkable that epilepsy and migraine are similar diseases with many parallel clinical features, as well as sharing common pathophysiological mechanisms. However, the pathogenetic role of hippocampal sclerosis (HS) in epilepsy and headache coexistence has not been clarified. In this study, we aimed to investigate the frequency of headache/migraine and the relationship between headache and HS lateralizations in patients with mesial temporal lobe epilepsy (MTLE), accompanied by HS. Methods: Consecutive patients with mesial temporal lobe epilepsy with hippocampal sclerosis (HS–MTLE) followed up in epilepsy outpatient clinic were included in this study, with their demographic and clinical characteristics, HS lateralization, and side (unilateral-right-left, bilateral), which were recorded. Using the questionnaires, the type of headache [migraine, tension headache (TTH)] was determined. Patients in whom migraine and TTH could not be completely separated were recruited for the unclassified group. The temporal relationship of headache and seizures (peri-ictal and/or interictal), pain lateralization, and side (unilateral-right-left, bilateral, unilateral + bilateral) were likewise determined. Results: There were 56 patients (30 females, 26 males; mean age 36.9 ± 12.1 years; mean epilepsy duration 19.3 ± 12.5 years) included in the study. Thirty-one patients (55.4%) stated they had a headache: of these, eighteen (32.1%) had migraine and 9 (16.1%) had TTH. Migraine accounted for 58.1% of headaches and TTHs was 29%. Headache was unilateral in 15 patients, and bilateral or bilateral + unilateral in 16 patients. Of patients with migraine, pain was unilateral in 10, and bilateral or bilateral + unilateral in 8. HS was right-sided in 24 patients, left-sided in 30 patients, and bilateral in 2 patients. In patients with right-sided HS, it was an ipsilateral headache; bilateral headache was found to be more common in patients with left-sided HS (p = 0.029). No relationship was found between the lateralization of the headache and the side of HS in patients with migraine. Conclusion: The results of our study showed that approximately half the patients with HS-MTLE did have a headache, with one third noting migraine type headache; this highlighted that HS may play a pathogenetic role in the development of headache, especially migraine, in patients with epilepsy. Further comprehensive studies will enable us to understand whether accompanying headache, especially migraine attacks in patients with epilepsy, can be determinant for HS-MTLE, as well as if it has a lateralizing value for HS.