OBJECTIVES: Isavuconazole is an antifungal azole indicated in adults for the treatment of invasive aspergillosis (IA) and of mucormycosis in patients for whom amphotericin B is inappropriate. This study evaluated the cost-effectiveness of isavuconazole versus voriconazole in the treatment of invasive fungal infections (IFI) in Portugal. METHODS: A decision-analytical model was adapted to predict life-years (LY), quality-adjusted life years (QALYs), and associated costs (€) in the treatment of IFI patients in Portugal. The decision-tree model tracks the patient pathway prior to differential pathogen diagnosis, from initial symptoms to resolution of infection (survival) or death. Transition and adverse event probabilities were based on randomized clinical trials (SECURE and VITAL studies). Since voriconazole is not indicated for mucormycosis, patients in the model were assumed to start treatment for IA with voriconazole and switch to liposomal amphotericin-B at mucormycosis diagnosis confirmation. Resource use and costs were extracted from Portuguese official sources (€, 2020) and from the literature. Results were extrapolated to a lifetime horizon using the average life expectancy for the underlying health conditions of IFI patients and Portuguese-specific utilities. A National Health Service perspective was adopted, and results were discounted at 4%. Parameter uncertainty was addressed via deterministic (including scenario analyses) and probabilistic sensitivity analysis (PSA). RESULTS: Average cost per patient for isavuconazole and generic voriconazole treatment were 19,606€ and 16,198€, respectively. The average effectiveness gain with isavuconazole treatment was +0.46LY and +0.32QALY when compared to voriconazole, resulting in an incremental cost-effectiveness ratio of 7,385€/LY and 10,668€/QALY, respectively. The scenario analysis for renal impaired patients showed isavuconazole dominance (-5,751€, +0.39QALY). The model results showed robustness in most scenario analyses and in the PSA. CONCLUSIONS: Isavuconazole is a cost-effective treatment when compared to generic voriconazole in patients with possible IA at usually accepted thresholds, and a dominant option in the subpopulation of patients with renal impairment.