AbstractBackground and PurposeHypoechogenicity of the raphe nuclei (hR) has been related to major depression. Comorbidity between migraine and depression is bidirectional postulating a common mechanism of serotonergic dysfunction. We aimed to investigate the association between migraine and hR and its role as biomarker of migraine‐associated depression and disease severity.MethodsThis is a single‐center cross‐sectional descriptive study. We included consecutive patients with episodic (EM) and chronic migraine (CM). We collected their comorbidities, analgesic consumption, hospital anxiety and depression scale (HADS), disability, and impact on quality of life associated with migraine. We also included a group of control subjects, matched for age and sex with the patients. In both groups, hR was assessed by means of transcranial sonography. We performed a meta‐analysis of the studies investigating the association between migraine and hR.ResultsA total of 107 subjects were included (57 cases and 50 controls). hR rate was lower in controls than in migraine patients (22.2% vs. 42.9%, p = .02) with a progressive increase in EM and CM groups respect to the control group (33.3% and 50% vs. 22.2%, respectively; p = .03). Among patients, hR was not associated with depression, higher HADS score, greater migraine‐related disability, or higher consumption of analgesic medication. The meta‐analysis showed a significant association between migraine and hR (odds ratio = 2.16; 95% confidence interval: 1.42‐3.29).ConclusionhR is more prevalent in migraine patients than in controls and, in our population, its prevalence increases in a stepwise manner in patients with EM and CM. These findings support the role of raphe nuclei in migraine pathophysiology.