OBJECTIVES: Toenail onychomycosis is the most common nail fungal infection. If left untreated, it can evolve into a more severe stage that can involve the matrix. The clinical management of patients remains constraining and long. In addition, relapses occur frequently after antifungal treatment. This has significant socio-economic impact. Combining topical and oral antifungals can increase cure rates and decrease treatment duration. The OnychoTree project aims at providing an evaluation tool to estimate economic consequences of the management of severe toenail onychomycosis in Europe. METHODS: The methodology for OnychoTree development follows a rigorous stepwise design to obtain an international model, valid for use across 17 countries: 1) an extensive literature review of international data on toenail onychomycosis; 2) the design of a core clinical-management decision tree; 3) the validation and completion of the core model (treatment patterns and medical resource use) by an expert panel of 12 dermatologists from six countries; 4) expansion and validation of the model to 11 additional countries through advisory panel interviews assessing national specificities (disease management and associated costs); 5) a meta-analysis of efficacy rates from relevant clinical trials of antifungals; 6) cost-effectiveness analyses. RESULTS: The initial common model was designed from the available international literature. The expert panel clinicians confirmed their interest for: 1) a clinical management model, and 2) cost-effectiveness evaluation including new combination therapies. They requested adaptations to reflect country-specific medical practice. After adaptation, they validated the core European pharmacoeconomic model. Advisory panel interviews confirmed these results, focusing on the need for country-specific analyses based on a common decision tree. CONCLUSIONS: Cost-effectiveness analyses including the 17 country-specific data will be performed with the final model. These European results will make both medical professionals and the public aware of the possible improvement in health-care resource use for the management of severe toenail onychomycosis.