Context: The substantial functional impairment associated with migraine has both physical and emotional ramifications. Mood disorders are often comorbid in patients with migraine and are known to adversely affect migraine activity. Objectives: To explore the effects of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) on pain and mood disorders in patients with high-frequency migraine. Methods: Retrospective review of the medical records of patients with high-frequency migraine who were treated with OMTh at the Headache Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia from 2011 to 2015. Clinical assessments were made using the Headache Disability Inventory (HDI), the Headache Impact Test (HIT-6), the Hamilton Depression Rating Scale (HDRS), and the State-Trait Anxiety Inventory (STAI) forms X-1 and X-2. Results: Medical records of 11 patients (6 women; mean age, 47.5 [7.8] years) with a diagnosis of high-frequency migraine who participated in an OMTh program met the inclusion criteria and were included in the study. When the questionnaire scores obtained at the first visit (T0) and after 4 OMTh sessions (T1) were compared, significant improvement in scores were observed on STAI X-2 (T0: 43.18 [2.47]; T1: 39.45 [2.52]; P<.05), HIT-6 (T0: 63 [2.20]; T1: 56.27 [2.24]; P<.05), and HDI (T0: 58.72 [6.75]; T1: 45.09 [7.01]; P<.05). Conclusion: This preliminary study revealed that patients with high-frequency migraine and comorbid mood disorders showed significant improvement after four 45-minute OMTh sessions. Further investigation into the effects of OMTh on pain and mood disorders in patients with high-frequency migraine is needed.