Background: Surgical treatment strategies for mitral valve disease have progressively shifted toward repair given the better survival outcomes with this type of intervention. However, valve repairs and valve replacement may require reoperations with time. In the absence of clinical trials assessing the effectiveness of various mitral surgical treatments with time, we propose to develop cost-effectiveness models to compare sequential treatment strategies. Methods: Three simulation models were carried out to assess the cost-effectiveness of mitral valve repair as first-line treatment, compared with either mechanical or biologic valve replacements. Efficacy data were derived from both the published literature and from a specific clinical cohort of 582 patients treated for this condition. Using the French public health care system perspective, relevant direct costs were derived using a local resource utilization assessment and official costing data sources. Results: Over 10 years, costs per success were significantly lower (p < 0.01) for the mitral valve repair strategy versus biologic or mechanical valve replacements (€35,550, €49,492, and €54,634 per success, respectively). Over 20 years, costs per success were significantly lower (p < 0.01) for the mechanical valve replacement strategy compared with the mitral valve repair and biologic valve replacement (€94,763, €100,053, and €147,484 per success, respectively). Conclusions: Considering the increased referral rate in older patients with degenerative mitral valve disease, and their shorter life expectancy, these results show that when medically required and technically practicable, mitral valve repair should be considered as the first-line strategy. © 2013 The Society of Thoracic Surgeons.