e New approaches of empirical antifungal therapy (EAT) in selected hematological patients with persistent febrile neutropenia (PFN) have been proposed in recent years, but their cost-effectiveness has not been studied. The aim of this study was to compare the cost-effectiveness of two different approaches of EAT in hematological patients with PFN: the diagnosis-driven antifungal therapy (DDAT) approach versus the standard approach of EAT. A decision tree to assess the cost-effectiveness of both approaches was developed. Outcome probabilities and treatment pathways were extrapolated from two studies: a prospective cohort study following the DDAT approach and a randomized clinical trial following the standard approach. Uncertainty was undertaken through sensitivity analyses and Monte Carlo simulation. The average effectiveness and economic advantages in the DDAT approach compared to the standard approach were 2.6% and €5,879 (33%) per PFN episode, respectively. The DDAT was the dominant approach in the 99.5% of the simulations performed with average cost-effectiveness per PFN episode of €32,671 versus €52,479 in the EAT approach. The results were robust over a wide range of variables. The DDAT approach is more costeffective than the EAT approach in the management of PFN in hematological patients. Invasive fungal infection (IFI) is a serious health problem in hematological patients and hematopoietic stem cell transplant (HSCT) recipients, resulting in a significant morbidity and mortality rate (1-3). Persistent febrile neutropenia (PFN) is a common clinical presentation of IFI in hematological patients. For this reason, during the last 3 decades, the standard approach recommended by the Infectious Diseases Society of America (IDSA) and other international societies for the management of persistent fever in neutropenic hematological patients has been indicating empirical antifungal therapy (EAT) in every patient, with the main objective of improving the outcome of IFI by prompt therapy (4, 5). However, the relatively low incidence of IFI in the whole hematological population, the risk of overtreatment with expensive drugs, and the potential appearance of adverse effects and antifungal resistance selection (6, 7) have made IFIs a safety and economic problem since the optimization of the health care budget is a major priority for all health care systems. Furthermore, the improvement of diagnostic procedures and the efficacy of new antifungal drugs have changed dramatically over the years (8, 9), allowing for new approaches for the management of this syndrome (8,(10)(11)(12)(13)(14), and even updated guidelines consider acceptable other more rational antifungal therapy approaches in a subset of high risk patients, although it is still considered as an experimental practice (4). The Andalusian Society of Infectious Diseases (SAEI) (12) proposed a diagnostic and therapeutic approach based on risk profile and driven by clinical criteria for selecting those patients with PFN who do not need antifungal therapy, avoiding ove...

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