Background <p>Chronic Migraine associated to Medication Overuse Headache (CM-MOH) causes considerable costs in reason of healthcare costs and loss of productivity. Recently, a mindfulness-based program added to treatment as usual (TaU) proved efficacy compared to TaU alone in patients with CM-MOH. This study aims to assess the cost-efficacy of such multimodal treatment protocol.</p> Methods <p>Patients with CM-MOH filled in a specific protocol aimed to assess direct healthcare costs, direct non-medical costs, and indirect costs, referred to the three months before starting the treatment protocol. Repeated measure analyses were employed to compare total costs’ reductions between the two group of patients. Then, we compared the delta in total costs after allocation to the two treatment arms using the independent-sample t-test.</p> Results <p>154 patients completed the 12-months follow-up. Over the period, CM-MOH cost was reduced from 2620€ (95% CI: 2146–3094€) to 1603€ (95% CI: 1182–2023€) in the TaU group, and from 2978€ (95% CI: 2293–3656€) to 752€ (95% CI: 539–965€) in the TaU + MIND group. The time*group interaction analysis on cost reduction indicated a significant difference (F = 2.95_3,149; <i>p</i> =.035) with a moderate effect size (partial η² = 0.056). The average difference on one-year cost after randomization was 2582€ favoring patients in the TaU + MIND group: such a figure is higher than the reimbursement from the Lombardia Region Health System for mindfulness-based sessions implementation (57€ per patient).</p> Conclusions <p>This study supports the cost-efficacy of adding six weekly group sessions of mindfulness practice to TaU for the treatment of CM-MOH.</p> Trial registration <p>NCT03671681 (clinicaltrials.gov 13/09/2018).</p>